Solid forms of a CDK4 inhibitor

Abstract

The present invention relates to crystalline and amorphous forms of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol, pharmaceutical compositions comprising such solid forms, and the use of such solid forms and pharmaceutical compositions for the treatment of cancer.

Description

Background of the Invention Technical Field

[0001] This invention relates to a solid form of 1,5-dehydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (also referred to herein as PF-07220060), to pharmaceutical compositions comprising such a solid form, and to the use of such a solid form and pharmaceutical composition for the treatment of cancer.

[0002] Description of related technologies

[0003] Compound 1,5-dehydr-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060) is a potent inhibitor of cyclin-dependent kinase 4 (CDK4), and its structure is as follows:

[0004]

[0005] The preparation of PF-07220060 as a crystalline hydrate (form 1) is disclosed in International Patent Publication No. WO2019 / 207463 and U.S. Patent No. 10,233,188, the full contents of which are incorporated herein by reference.

[0006] This invention provides PF-07220060 in solid form, which has desired properties such as high crystallinity, high purity, low hygroscopicity, favorable solubility or mechanical properties, prepareability and / or favorable stability. Invention Overview

[0008] This invention provides 1,5-dehydr-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060) in solid form.

[0009] In some aspects and embodiments, the present invention provides a crystalline form (form 2) of the PF-07220060 monohydrate, as further described herein.

[0010] In one aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, which has:

[0011] (1) Powder X-ray diffraction (PXRD) pattern (2θ) containing: (a) one, two, three, four, five or more peaks selected from the peaks in Table 1 (units °2θ ± 0.2°2θ); or (b) in substantially the same order as the peaks in Table 1. Figure 1 Peaks at the same 2θ value;

[0012] (2) Raman spectrum, including: (a) values ​​selected from Table 2 (unit: cm) -1 ±2cm -1 A group consisting of one, two, three, four, five or more wavenumbers (cm) -1 (a) value; or (b) substantially the same as Figure 2 The same wave number (cm) -1 )value;

[0013] (3) 13 C solid-state NMR spectra (ppm) comprising: (a) one, two, three, four, five, or more than five resonance (ppm) values ​​selected from the values ​​in Table 3 (in ppm ± 0.2 ppm); or (b) substantially the same as... Figure 3 The same resonance (ppm) value; or

[0014] (4) 19 F solid-state NMR spectrum (ppm), comprising: (a) one or two resonance (ppm) values ​​selected from the group of values ​​(ppm ± 0.2 ppm) in Table 4; or (b) substantially the same as... Figure 4 The same resonance (ppm) value;

[0015] Or any combination of two or more of (1)(a) to (b), (2)(a) to (b), (3)(a) to (b) and (4)(a) to (b), provided that they do not contradict each other.

[0016] In another aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 9.6, 11.8, and 14.7°2θ ± 0.2°2θ.

[0017] In another aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, having crystalline masses of 1484, 1555, and 1587 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0018] In another aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having resonance (ppm) values ​​of 22.8 and 163.0 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0019] In another aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having resonance (ppm) values ​​comprising -126.1 and -125.6 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0020] In another aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, having: (a) powder X-ray diffraction (PXRD) patterns containing peaks at 2θ values ​​of 9.6, 11.8, and 14.7°2θ ± 0.2°2θ; and (b) peaks containing peaks at 1484, 1555, and 1587 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 (c) Raman spectra of values ​​of 22.8 and 163.0 ppm ± 0.2 ppm; 13 C solid-state NMR spectrum; or (d) resonance (ppm) values ​​including -126.1 and -125.6 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum; or any combination of two or more of (a), (b), (c) and (d).

[0021] In some aspects and embodiments, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060 according to aspects or embodiments further described herein.

[0022] In other aspects and embodiments, the present invention provides an anhydrous crystalline form (form 11) of PF-07220060 according to aspects or embodiments further described herein.

[0023] In other aspects and embodiments, the present invention provides an amorphous form (form 8) of PF-07220060 according to aspects or embodiments further described herein.

[0024] In another aspect, the present invention provides a pharmaceutical composition comprising a crystalline or amorphous form of PF-07220060 as described in any of the aspects or embodiments herein, and a pharmaceutically acceptable carrier or excipient. In a preferred embodiment, the pharmaceutical composition comprises crystalline PF-07220060 monohydrate (form 2). In some embodiments, the pharmaceutical composition comprises anhydrous crystalline PF-07220060 (form 6). In some embodiments, the pharmaceutical composition comprises anhydrous crystalline PF-07220060 (form 11). In some embodiments, the pharmaceutical composition comprises amorphous PF-07220060 (form 8).

[0025] In another aspect, the present invention provides a method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of crystalline or amorphous form of PF-07220060 according to any of the aspects or embodiments described herein, or a pharmaceutical composition comprising crystalline or amorphous form of PF-07220060.

[0026] In another aspect, the present invention provides the use of PF-07220060 in crystalline or amorphous form according to any of the aspects or embodiments described herein, or a pharmaceutical composition comprising PF-07220060 in crystalline or amorphous form for the treatment of cancer.

[0027] In another aspect, the present invention provides the use of PF-07220060 in crystalline or amorphous form according to any of the aspects or embodiments described herein, or a pharmaceutical composition comprising PF-07220060 in crystalline or amorphous form, in the preparation of a medicament for treating cancer.

[0028] In a preferred embodiment of the above-described method and use, the method or use includes crystalline PF-07220060 monohydrate (Form 2). In some embodiments, the method or use includes anhydrous crystalline PF-07220060 (Form 6). In some embodiments, the method or use includes anhydrous crystalline PF-07220060 (Form 11). In some embodiments, the method or use includes amorphous PF-07220060 (Form 8).

[0029] In another aspect, the present invention provides a crystalline or amorphous form of PF-07220060 according to any of the aspects or embodiments described herein, or a pharmaceutical composition comprising a crystalline or amorphous form of PF-07220060 for the treatment of cancer. In a preferred embodiment, the crystalline form is crystalline PF-07220060 monohydrate (form 2). In some embodiments, the crystalline form is anhydrous crystalline PF-07220060 (form 6). In some embodiments, the crystalline form is anhydrous crystalline PF-07220060 (form 11). In some embodiments, the amorphous form is amorphous PF-07220060 (form 8).

[0030] Brief description of the attached diagram

[0031] Figure 1 PXRD pattern of crystalline PF-07220060 monohydrate (form 2).

[0032] Figure 2 FT-Raman spectrum of crystalline PF-07220060 monohydrate (form 2).

[0033] Figure 3 Carbon CPMAS spectrum of crystalline PF-07220060 monohydrate (form 2) (# indicates rotating sideband).

[0034] Figure 4 Fluorine MAS spectrum of crystalline PF-07220060 monohydrate (form 2) (# indicates rotating sideband).

[0035] Figure 5 PXRD pattern of crystalline PF-07220060 hydrate (form 1).

[0036] Figure 6 Carbon CPMAS spectrum of crystalline PF-07220060 hydrate (form 1) (# indicates rotating sideband).

[0037] Figure 7 Fluorine MAS spectrum of crystalline PF-07220060 hydrate (form 1) (# indicates rotating sideband).

[0038] Figure 8 PXRD pattern of amorphous PF-07220060.

[0039] Figure 9 Adjusted DSC scan of amorphous PF-07220060.

[0040] Figure 10 FT-Raman spectrum of amorphous PF-07220060 (Form 8).

[0041] Figure 11 Carbon CPMAS spectrum of amorphous PF-07220060 (Form 8) (# indicates rotating sideband).

[0042] Figure 12 Fluorine MAS spectrum of amorphous PF-07220060 (Form 8) (# indicates rotating sideband).

[0043] Figure 13 PXRD pattern of anhydrous crystal PF-07220060 (Form 6).

[0044] Figure 14 FT-Raman spectrum of anhydrous crystal PF-07220060 (Form 6).

[0045] Figure 15 Carbon CPMAS spectrum of anhydrous crystal PF-07220060 (Form 6) (# indicates rotating sideband).

[0046] Figure 16 Fluorine MAS spectrum of anhydrous crystal PF-07220060 (form 6) (# indicates rotating sideband).

[0047] Figure 17 PXRD pattern of anhydrous crystal PF-07220060 (Form 11). Invention Details

[0049] The present invention will be more readily understood by referring to the following detailed description of embodiments of the invention and the examples contained herein. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be further understood that, unless expressly defined herein, the terminology used herein is provided with its conventional meaning as known in the related art.

[0050] The invention described herein may be suitably practiced in the absence of any elements not specifically disclosed herein. Therefore, for example, in each case herein, any one of the terms “comprising,” “substantially consisting of,” and “consisting of” may be replaced by any of the other two terms.

[0051] As used herein, unless otherwise specified, the singular forms “a / an” and “the” include plural references. For example, “a” substituent includes one or more substituents.

[0052] When considered by a person skilled in the art, unless otherwise specified, the term “about” means a value that falls within an acceptable standard error of the mean, typically such as plus or minus (±) 10%.

[0053] As used herein, the term "substantially identical" means taking into account typical variability for a particular method. For example, in the context of powder X-ray diffraction (PXRD) peak positions, the term "substantially identical" means taking into account typical variability in peak position and intensity. Those skilled in the art will understand that peak position (2θ) will exhibit some variability, typically up to ±0.2° (2θ) for crystalline forms or ±0.5° (2θ) for amorphous forms. Furthermore, those skilled in the art will understand that relative peak intensities will exhibit inter-device variability, as well as variability due to crystallinity, preferred orientation, the prepared sample surface, and other factors known to those skilled in the art, and should be considered only as qualitative measures. Similarly, Raman spectral wavenumber (cm²) -1 The value indicates variability, typically up to ±2 cm. -1 ,and 13 C and 19 Solid-state NMR spectra (ppm) show variability, typically up to ±0.2 ppm for crystalline forms or ±0.5 ppm for amorphous forms.

[0054] As used herein, the term “amorphous” refers to a solid material that (1) lacks three-dimensional order, or (2) exhibits less than three-dimensional order only at short distances (e.g., less than 1000 meters). The order is either present or both. Amorphous solids provide PXRD patterns that typically contain one or two broad peaks.

[0055] As used in this article, the term "crystallization" refers to a regular, repeating arrangement of molecules or planar outer surfaces. Crystallization forms can vary in thermodynamic stability, physical parameters, X-ray structure, and preparation methods.

[0056] The term "polymorph" or "polymorph" refers to the crystalline form of a compound that has a different spatial lattice arrangement compared to other crystalline forms of the same compound.

[0057] The term "solvent" describes a molecular complex comprising a compound (e.g., the active pharmaceutical ingredient (API) of a pharmaceutical product) and one or more solvent molecules (e.g., water or ethanol) in stoichiometric or non-stoichiometric amounts. When the solvent is tightly bound to the compound, the resulting complex will have a well-defined stoichiometry independent of humidity. However, when the solvent is weakly bound, as in channel solvates and hygroscopic compounds, the solvent content will depend on humidity and drying conditions. In such cases, the complex is typically non-stoichiometric.

[0058] The term "hydrate" describes a solvate containing a compound and a stoichiometric or non-stoichiometric amount of water. A "monohydrate" is a hydrate in which each molecule of the compound contains one molecule of water (i.e., a 1:1 stoichiometry of water to the compound).

[0059] The expression "substantially pure" means that a crystalline or amorphous form described as substantially pure contains less than 5% by weight, preferably less than 3% by weight, and more preferably less than 1% by weight of impurities, including any other physical form of the compound. Alternatively, a crystalline or amorphous form described as substantially pure may be expressed as >95% pure, preferably >97% pure, and more preferably >99% pure, in each case by weight of impurities (including any other physical form of the compound).

[0060] The crystalline and amorphous forms of PF-07220060 described in this paper can be characterized by the following methods: (1) powder X-ray diffraction (PXRD) (2θ); (2) Raman spectroscopy (cm). -1 (3) 13 C solid-state NMR spectrum (ppm); (4) 19 F solid-state NMR spectroscopy (ppm); or (5) differential scanning calorimetry (DSC) scan (Tg °C); or any combination of two or more of methods (1), (2), (3), (4) and (5).

[0061] In each of the aspects and embodiments of this paper characterized by PXRD, the value at 1.5418λ is used. Radiation-collected PXRD peaks.

[0062] Such solid forms can be further characterized by other techniques, such as Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), or differential thermal analysis (DTA).

[0063] In a preferred aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate. In some embodiments, the crystalline form (form 2) of PF-07220060 monohydrate is characterized by its powder X-ray diffraction (PXRD) pattern. In other embodiments, the crystalline form (form 2) of PF-07220060 monohydrate is characterized by its Raman spectroscopy. In other embodiments, the crystalline form (form 2) of PF-07220060 monohydrate is characterized by its... 13 Solid-state NMR spectroscopy characterization. In other embodiments, the crystalline form (form 2) of the PF-07220060 monohydrate is characterized by its... 19 Solid-state NMR spectroscopy characterization.

[0064] In another embodiment, the crystalline PF-07220060 monohydrate (form 2) is characterized by any combination of two or more of such methods. Exemplary combinations comprising two or more of the following are provided herein: powder X-ray diffraction (PXRD) pattern (2θ); Raman spectral wave value (cm²). -1 );13 C solid-state NMR spectrum (ppm); or 19 Solid-state NMR spectroscopy (ppm). In some embodiments, crystalline PF-07220060 monohydrate (form 2) was characterized by PXRD and Raman spectroscopy. In other embodiments, crystalline PF-07220060 monohydrate (form 2) was characterized by PXRD and Raman spectroscopy. 13 Solid-state NMR characterization. In other embodiments, crystalline PF-07220060 monohydrate (form 2) was characterized by PXRD and... 19 Solid-state NMR characterization. In other embodiments, crystalline PF-07220060 monohydrate (form 2) was characterized by... 19 Solid-state NMR and Raman characterization. In other embodiments, crystalline PF-07220060 monohydrate (form 2) was characterized by... 19 F solid-state NMR and 13 Solid-state NMR characterization. In other embodiments, crystalline PF-07220060 monohydrate (form 2) was characterized by PXRD, Raman spectroscopy, and... 13 Solid-state NMR characterization. In other embodiments, crystalline PF-07220060 monohydrate (form 2) was characterized by PXRD, Raman spectroscopy, and... 19 Solid-state NMR characterization.

[0065] In one aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, characterized by powder X-ray diffraction (PXRD) pattern.

[0066] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 9.6, 11.8, and 14.7°2θ ± 0.2°2θ.

[0067] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 9.6, 11.8, 12.4, and 14.7°2θ ± 0.2°2θ.

[0068] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 9.6, 11.8, 14.7, and 21.0°2θ ± 0.2°2θ.

[0069] In another embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 9.6, 11.8, 12.4, 14.7 and 21.0°2θ ± 0.2°2θ.

[0070] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having peaks at 2θ values ​​of 9.6, 11.8, and 14.7°2θ ± 0.2°2θ; and a powder X-ray diffraction (PXRD) pattern of one or both peaks selected from the group consisting of 12.4 and 21.0°2θ ± 0.2°2θ.

[0071] In another embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having a PXRD pattern containing three or more peaks at 2θ values ​​selected from the group consisting of 9.6, 11.8, 12.4, 14.7 and 21.0°2θ ± 0.2°2θ.

[0072] In another embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having a PXRD pattern comprising: (a) one, two, three, four, five, or more five peaks selected from groups of peaks (units °2θ ± 0.2 °2θ) in Table 1; or (b) peaks in relation to... Figure 1 The peaks are at essentially the same 2θ values.

[0073] In another aspect, the present invention provides a crystalline form (form 2) of the PF-07220060 monohydrate, characterized by Raman spectroscopy.

[0074] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, having crystalline precipitates of 1484, 1555, and 1587 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0075] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, having crystalline masses of 1387, 1484, 1555, and 1587 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0076] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, having crystalline masses of 1395, 1484, 1555, and 1587 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0077] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, having crystalline masses of 1387, 1395, 1484, 1555, and 1587 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0078] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, having crystalline precipitates of 1484, 1555, and 1587 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Value; and choose freely between 1387 and 1395 cm. -1 ±2cm -1 Raman spectra of one or two peaks in a group.

[0079] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, having a Raman spectrum comprising the following: (a) values ​​selected from Table 2 (unit: cm⁻¹). -1 ±2cm -1 A group consisting of one, two, three, four, five or more wavenumbers (cm) -1 (a) value; or (b) with Figure 2 The wave number (cm) is basically the same. -1 )value.

[0080] In another aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, which is obtained by... 13 Solid-state NMR spectral characterization.

[0081] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having resonance (ppm) values ​​of 22.8 and 163.0 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0082] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having resonance (ppm) values ​​of 22.8, 50.3, and 163.0 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0083] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having resonance (ppm) values ​​of 22.8, 109.8, and 163.0 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0084] In another embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having resonance (ppm) values ​​of 22.8, 129.1, and 163.0 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0085] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having a resonance (ppm) value comprising the following 13 Solid-state NMR spectra: 22.8 and 163.0 ppm ± 0.2 ppm; and one, two or three resonance (ppm) values ​​selected from the group consisting of 50.3, 109.8 and 129.1 ppm ± 0.2 ppm.

[0086] In another embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, which has 13 C solid-state NMR spectra (ppm) comprising: (a) one, two, three, four, five, or more than five resonance (ppm) values ​​selected from the values ​​in Table 3 (in ppm ± 0.2 ppm); or (b) with Figure 3 The resonance (ppm) values ​​are basically the same.

[0087] In another aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, which is obtained by... 19 Solid-state NMR spectroscopy characterization.

[0088] In one embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having a resonance (ppm) value of -126.1 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0089] In another embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having a resonance (ppm) value of -125.6 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0090] In a preferred embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate having resonance (ppm) values ​​of -126.1 and -125.6 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0091] In another embodiment, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, which has 19 F solid-state NMR spectrum (ppm), comprising: (a) one or two resonance (ppm) values ​​selected from the group of values ​​(ppm ± 0.2 ppm) in Table 4; or (b) with Figure 4 The resonance (ppm) values ​​shown are essentially the same.

[0092] In another aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, which has:

[0093] (a) Powder X-ray diffraction (PXRD) patterns of peaks at 2θ values ​​of 9.6, 11.8 and 14.7°2θ ± 0.2°2θ;

[0094] (b) Includes 1484, 1555 and 1587 cm -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values;

[0095] (c) Includes resonance (ppm) values ​​of 22.8 and 163.0 ppm ± 0.2 ppm 13 C solid-state NMR spectrum; or

[0096] (d) Resonance (ppm) values ​​including -126.1 and -125.6 ppm ± 0.2 ppm 19 F solid-state NMR spectrum;

[0097] Or any combination of two or more of (a), (b), (c) and (d).

[0098] In another aspect, the present invention provides a crystalline form (form 2) of PF-07220060 monohydrate, which has:

[0099] (1) Powder X-ray diffraction (PXRD) pattern of peaks at the following 2θ values:

[0100] (a) 9.6, 11.8 and 14.7°2θ±0.2°2θ;

[0101] (b) 9.6, 11.8, 12.4 and 14.7°2θ ± 0.2°2θ;

[0102] (c) 9.6, 11.8, 14.7 and 21.0°2θ ± 0.2°2θ; or

[0103] (d) 9.6, 11.8, 12.4, 14.7 and 21.0°2θ±0.2°2θ;

[0104] (2) Includes the following wavenumbers (cm) -1 Raman spectra of values:

[0105] (a) 1484, 1555 and 1587 cm -1 ±2cm -1 ;

[0106] (b) 1387, 1484, 1555 and 1587 cm -1 ±2cm -1 ;

[0107] (c) 1395, 1484, 1555 and 1587 cm -1 ±2cm -1 ;or

[0108] (d) 1387, 1395, 1484, 1555 and 1587 cm -1 ±2cm -1 ;

[0109] (3) Includes the following resonance (ppm) values 13 C solid-state NMR spectrum:

[0110] (a) 22.8 and 163.0 ppm ± 0.2 ppm;

[0111] (b) 22.8, 50.3 and 163.0 ppm ± 0.2 ppm;

[0112] (c) 22.8, 109.8 and 163.0 ppm ± 0.2 ppm;

[0113] (d) 22.8, 129.1 and 163.0 ppm ± 0.2 ppm;

[0114] (e) 22.8, 50.3, 109.8 and 163.0 ppm ± 0.2 ppm;

[0115] (f) 22.8, 50.3, 129.1 and 163.0 ppm ± 0.2 ppm;

[0116] (g) 22.8, 109.8, 129.1 and 163.0 ppm ± 0.2 ppm; or

[0117] (h) 22.8, 50.3, 109.8, 129.1 and 163.0 ppm ± 0.2 ppm;

[0118] or

[0119] (4) Includes the following resonance (ppm) values 19 F solid-state NMR spectrum:

[0120] (a) -126.1ppm ± 0.2ppm;

[0121] (b) -125.6ppm ± 0.2ppm; or

[0122] (c) -125.6 and -126.1 ppm ± 0.2 ppm;

[0123] Or any combination of two or more of (1)(a) to (d), (2)(a) to (d), (3)(a) to (h) and (4)(a) to (c).

[0124] In another aspect, the present invention provides a pharmaceutical composition comprising the crystalline form (form 2) of PF-07220060 monohydrate according to the aspects or embodiments described herein, and a pharmaceutically acceptable carrier or excipient.

[0125] In another aspect, the present invention provides a method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of a crystalline form (Form 2) of PF-07220060 monohydrate, or a pharmaceutical composition comprising a crystalline form (Form 2) of PF-07220060 monohydrate according to the aspects or embodiments described herein.

[0126] In another aspect, the present invention provides a method for treating cancer in a subject in need, comprising administering to the subject a certain amount of crystalline form (form 2) of PF-07220060 monohydrate, or a pharmaceutical composition comprising crystalline form (form 2) of PF-07220060 monohydrate according to the aspects or embodiments described herein, and a certain amount of additional anticancer agent, wherein the amount of PF-07220060 monohydrate (form 2) and the additional anticancer agent together is effective in treating cancer.

[0127] In another aspect, the present invention provides the use of a crystalline form (Form 2) of PF-07220060 monohydrate, or a pharmaceutical composition comprising the crystalline form (Form 2) of PF-07220060 monohydrate according to the aspects or embodiments described herein, for the treatment of cancer.

[0128] In yet another aspect, the present invention provides the use of the crystalline form (form 2) of the PF-07220060 monohydrate according to the aspects or embodiments described herein in the preparation of a medicament for treating cancer.

[0129] In another aspect, the present invention provides a crystalline form (Form 2) of PF-07220060 monohydrate or a pharmaceutical composition comprising the crystalline form (Form 2) of PF-07220060 monohydrate according to the aspects or embodiments described herein, for the treatment of cancer.

[0130] In each of the aspects and embodiments of the crystalline PF-07220060 monohydrate (Form 2) described herein, the crystalline form may be a substantially pure crystalline form (Form 2) of the PF-07220060 monohydrate.

[0131] Each embodiment described herein for crystalline PF-07220060 monohydrate (Form 2) may be combined with other such embodiments, provided that these embodiments do not contradict each other.

[0132] In another aspect, the present invention provides an amorphous form (form 8) of PF-07220060. In some embodiments, the amorphous form (form 8) of PF-07220060 is characterized by its powder X-ray diffraction (PXRD) pattern. In some embodiments, the amorphous form (form 8) of PF-07220060 is characterized by differential scanning calorimetry (DSC). In further embodiments, the amorphous form (form 8) of PF-07220060 is characterized by a combination of PXRD and DSC. In other embodiments, the amorphous form (form 8) of PF-07220060 is characterized by its Raman spectroscopy. In other embodiments, the amorphous form (form 8) of PF-07220060 is characterized by its Raman spectroscopy. 13 Solid-state NMR spectroscopy characterization. In other embodiments, the amorphous form (form 8) of PF-07220060 is characterized by its... 19 Solid-state NMR spectroscopy characterization. In another embodiment, the amorphous form (form 8) of PF-07220060 is characterized by any combination of two or more of these methods. In some such embodiments, the amorphous form (form 8) of PF-07220060 is characterized by... 19 F solid-state NMR and13 Solid-state NMR characterization.

[0133] In one embodiment, the present invention provides an amorphous form (form 8) of PF-07220060. In another embodiment, the present invention provides an amorphous form (form 8) of PF-07220060 characterized by its powder X-ray diffraction (PXRD) pattern. In some such embodiments, the present invention provides an amorphous form (form 8) of PF-07220060 having a powder X-ray diffraction (PXRD) pattern (2θ) comprising: (a) a broad peak at a diffraction angle (2θ) of about 4 to about 40°2θ ± 0.5°2θ; or (b) a peak at a diffraction angle (2θ) of about 4 to about 40°2θ ± 0.5°2θ. Figure 8 Peaks at essentially the same 2θ value.

[0134] In another embodiment, the present invention provides an amorphous form (form 8) of PF-07220060, characterized by DSC. In some such embodiments, the present invention provides an amorphous form (form 8) of PF-07220060 having: (a) a glass transition temperature (Tg) of about 102 °C, as measured by DSC at a ramp rate of 2 °C / min; or (b) with Figure 9 The DSC temperature spectrum is basically the same.

[0135] In another aspect, the present invention provides an amorphous form (form 8) of PF-07220060, which is characterized by Raman spectroscopy.

[0136] In one embodiment, the present invention provides an amorphous form (form 8) of PF-07220060, which has a cross-sectional area of ​​1430 and 1453 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra with values ​​of 1430 and 1574 cm⁻¹. In one embodiment, the present invention provides an amorphous form (form 8) of PF-07220060, which has Raman spectra with values ​​of 1430 and 1574 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra with values ​​of 1430, 1453, and 1574 cm⁻¹. In one embodiment, the present invention provides an amorphous form (form 8) of PF-07220060, which has Raman spectra with values ​​of 1430, 1453, and 1574 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0137] In one embodiment, the present invention provides an amorphous form (form 8) of PF-07220060 having a Raman spectrum comprising: (a) values ​​selected from Table 7 (unit: cm⁻¹) -1±2cm -1 A group consisting of one, two, three, four, five or more wavenumbers (cm) -1 (a) value; or (b) with Figure 10 The wave number (cm) is basically the same. -1 )value.

[0138] In another aspect, the present invention provides an amorphous form (form 8) of PF-07220060, which is achieved by... 13 Solid-state NMR spectral characterization.

[0139] In one embodiment, the present invention provides an amorphous form (form 8) of PF-07220060 having resonance (ppm) values ​​of 20.9, 49.3, and 116.6 ppm ± 0.5 ppm. 13 Solid-state NMR spectroscopy. In one embodiment, the present invention provides an amorphous form (form 8) of PF-07220060, having resonance (ppm) values ​​comprising 20.9 and 49.3 ± 0.5 ppm. 13 Solid-state NMR spectroscopy. In one embodiment, the present invention provides an amorphous form (form 8) of PF-07220060, having resonance (ppm) values ​​of 20.9 and 116.6 ppm ± 0.5 ppm. 13 C solid-state NMR spectroscopy. In one embodiment, the present invention provides an amorphous form (form 8) of PF-07220060, having resonance (ppm) values ​​of 49.3 and 116.6 ppm ± 0.5 ppm. 13 C solid-state NMR spectroscopy.

[0140] In another embodiment, the present invention provides an amorphous form (form 8) of PF-07220060, which has 13 C solid-state NMR spectra (ppm) comprising: (a) one, two, three, four, five, or more than five resonance (ppm) values ​​selected from the values ​​in Table 8 (unit: ppm ± 0.5 ppm); or (b) with Figure 11 The resonance (ppm) values ​​are basically the same.

[0141] In another aspect, the present invention provides an amorphous form (form 8) of PF-07220060, which is achieved by... 19 Solid-state NMR spectral characterization. In one embodiment, the present invention provides an amorphous form (form 8) of PF-07220060, having a resonance (ppm) value of -127.5 ppm ± 0.5 ppm. 19F solid-state NMR spectroscopy. In another embodiment, the present invention provides an amorphous form (form 8) of PF-07220060, which has 19 F solid-state NMR spectra (ppm), including: (a) resonance (ppm) values ​​in Table 9 (units ppm ± 0.5ppm); or (b) with Figure 12 The resonance (ppm) values ​​shown are essentially the same.

[0142] In one embodiment, the present invention provides an amorphous form (form 8) of PF-07220060 having a resonance (ppm) value of -127.5ppm ± 0.5ppm. 19 F solid-state NMR spectrum; and resonance (ppm) values ​​including the following 13 C solid-state NMR spectra: (a) 20.9, 49.3 and 116.6 ppm ± 0.5 ppm; (b) 20.9 and 49.3 ppm ± 0.5 ppm; (c) 20.9 and 116.6 ppm ± 0.5 ppm; or (d) 49.3 and 116.6 ppm ± 0.5 ppm.

[0143] In another embodiment, the present invention provides an amorphous form (form 8) of PF-07220060, which has:

[0144] (1) Contains the following powder X-ray diffraction (PXRD) pattern (2θ):

[0145] (a) A broad peak at a diffraction angle (2θ) of approximately 4 to approximately 40°2θ ± 0.5°2θ; or

[0146] (b) in relation to Figure 8 Peaks at essentially the same 2θ value; or

[0147] (2) Includes the following DSC temperature spectrum:

[0148] (a) Glass transition temperature (Tg) of approximately 102 °C, as measured by DSC at a ramp rate of 2 °C / min; or

[0149] (b) and Figure 9 The DSC temperature spectra are basically the same; or

[0150] (3) Includes the following 19 F solid-state NMR spectrum:

[0151] (a) Resonance (ppm) value of -127.5ppm ± 0.5ppm; or

[0152] (b) and Figure 12 The resonance (ppm) values ​​shown are essentially the same; or

[0153] (4) Includes the following resonance (ppm) values 13 C solid-state NMR spectrum:

[0154] (a) 20.9, 49.3 and 116.6 ppm ± 0.5 ppm;

[0155] (b) 20.9 and 49.3 ppm ± 0.5 ppm;

[0156] (c) 20.9 and 116.6 ppm ± 0.5 ppm; or

[0157] (d) 49.3 and 116.6 ppm ± 0.5 ppm;

[0158] Or any combination of two or more of (1)(a) to (b), (2)(a) to (b), (3)(a) to (b) and (4)(a) to (d).

[0159] In another aspect, the present invention provides a pharmaceutical composition comprising an amorphous form (form 8) of PF-07220060 according to the aspects or embodiments described herein, and a pharmaceutically acceptable carrier or excipient.

[0160] In another aspect, the present invention provides a method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of an amorphous form (form 8) of PF-07220060, or a pharmaceutical composition comprising an amorphous form (form 8) of PF-07220060 according to the aspects or embodiments described herein.

[0161] In another aspect, the present invention provides a method of treating cancer in a subject in need, comprising administering to the subject an amount of an amorphous form (form 8) of PF-07220060, or a pharmaceutical composition comprising an amorphous form (form 8) of PF-07220060 according to the aspects or embodiments described herein and an amount of a further anticancer agent, wherein the amount of PF-07220060 and the further anticancer agent together is effective in treating cancer.

[0162] In another aspect, the present invention provides the use of an amorphous form (form 8) of PF-07220060, or a pharmaceutical composition comprising an amorphous form (form 8) of PF-07220060 according to the aspects or embodiments described herein, for the treatment of cancer.

[0163] In yet another aspect, the present invention provides the use of an amorphous form (form 8) of PF-07220060, or a pharmaceutical composition comprising an amorphous form (form 8) of PF-07220060 according to the aspects or embodiments described herein, in the preparation of a medicament for treating cancer.

[0164] In another aspect, the present invention provides an amorphous form (form 8) of PF-07220060, or a pharmaceutical composition comprising an amorphous form (form 8) of PF-07220060 according to the aspects or embodiments described herein, for the treatment of cancer.

[0165] In each of the aspects and embodiments of the amorphous PF-07220060 (Form 8) described herein, the amorphous form may be a substantially pure amorphous form (Form 8) of PF-07220060.

[0166] Each embodiment described herein for amorphous PF-07220060 (Form 8) may be combined with other such embodiments, provided that these embodiments do not contradict each other.

[0167] In one aspect, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060. In some embodiments, the anhydrous crystalline form (form 6) of PF-07220060 is characterized by its powder X-ray diffraction (PXRD) pattern. In other embodiments, the anhydrous crystalline form (form 6) of PF-07220060 is characterized by its Raman spectroscopy. In other embodiments, the anhydrous crystalline form (form 6) of PF-07220060 is characterized by its... 13 Solid-state NMR spectroscopy characterization. In other embodiments, the anhydrous crystalline form (form 6) of PF-07220060 is characterized by its... 19 Solid-state NMR spectroscopy characterization.

[0168] In another embodiment, anhydrous crystalline PF-07220060 (Form 6) is characterized by any combination of two or more of such methods. Exemplary combinations comprising two or more of the following are provided herein: powder X-ray diffraction (PXRD) pattern (2θ); Raman spectral wave value (cm²). -1 ); 13 C solid-state NMR spectrum (ppm); or 19 Solid-state NMR spectroscopy (ppm). In some embodiments, anhydrous crystalline PF-07220060 (form 6) was characterized by PXRD and Raman spectroscopy. In other embodiments, anhydrous crystalline PF-07220060 (form 6) was characterized by PXRD and Raman spectroscopy. 13Solid-state NMR characterization. In other embodiments, anhydrous crystalline PF-07220060 (form 6) was characterized by PXRD and... 19 Solid-state NMR characterization. In other embodiments, anhydrous crystalline PF-07220060 (form 6) was characterized by... 19 Solid-state NMR and Raman characterization. In other embodiments, anhydrous crystallized PF-07220060 (form 6) was characterized by... 19 F solid-state NMR and 13 Solid-state NMR characterization. In other embodiments, anhydrous crystalline PF-07220060 (form 6) was characterized by PXRD, 19 F solid-state NMR and 13 Solid-state NMR characterization. In other embodiments, anhydrous crystalline PF-07220060 (form 6) was characterized by PXRD, Raman spectroscopy, and... 19 Solid-state NMR characterization.

[0169] In one aspect, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, characterized by powder X-ray diffraction (PXRD) patterns.

[0170] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060 having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 6.8 and 10.1°2θ ± 0.2°2θ.

[0171] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060 having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 6.8, 10.1, and 12.2°2θ ± 0.2°2θ.

[0172] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060 having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 6.8, 10.1, and 17.8°2θ ± 0.2°2θ.

[0173] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060 having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 6.8, 10.1, 12.2, and 17.8°2θ ± 0.2°2θ.

[0174] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060 having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 8.5, 10.1, and 13.8°2θ ± 0.2°2θ.

[0175] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060 having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 6.8, 8.5, and 13.8°2θ ± 0.2°2θ.

[0176] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060 having powder X-ray diffraction (PXRD) patterns of peaks at 2θ values ​​of 6.8, 8.5, 10.1, and 13.8°2θ ± 0.2°2θ.

[0177] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060 having a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 6.8, 8.5, 10.1, 12.2, and 13.8°2θ ± 0.2°2θ.

[0178] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060 having a powder X-ray diffraction (PXRD) pattern containing peaks at the following 2θ values: 6.8 and 10.1°2θ ± 0.2°2θ; and one, two, three, or four peaks selected from the group consisting of 8.5, 12.2, 13.8, and 17.8°2θ ± 0.2°2θ.

[0179] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060 having a PXRD pattern containing three or more peaks at 2θ values ​​selected from the group consisting of 6.8, 8.5, 10.1, 12.2, 13.8 and 17.8°2θ±0.2°2θ.

[0180] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having a PXRD pattern comprising: (a) one, two, three, four, five, or more five peaks selected from groups of peaks (units °2θ ± 0.2 °2θ) in Table 10; or (b) peaks in relation to... Figure 13 The peaks are at essentially the same 2θ values.

[0181] In another aspect, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, which is characterized by Raman spectroscopy.

[0182] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, which has a content of 1436 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0183] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having a crystal content of 1436 and 1566 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0184] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having a crystal size of 1436 and 1465 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0185] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having crystalline masses of 1436, 1465, and 1566 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0186] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, which has a Raman spectrum comprising: (a) values ​​selected from Table 11 (unit: cm⁻¹). -1 ±2cm -1 A group consisting of one, two, three, four, five or more wavenumbers (cm) -1 (a) value; or (b) with Figure 14 The wave number (cm) is basically the same. -1 )value.

[0187] In another aspect, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, which is obtained by... 13 Solid-state NMR spectral characterization.

[0188] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having resonance (ppm) values ​​of 54.7 and 112.6 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0189] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having resonance (ppm) values ​​of 54.7 and 132.8 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0190] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having resonance (ppm) values ​​of 112.6 and 132.8 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0191] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having resonance (ppm) values ​​of 54.7, 112.6, and 132.8 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0192] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having resonance (ppm) values ​​of 49.2, 54.7, and 112.6 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0193] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having resonance (ppm) values ​​of 49.2, 54.7, and 132.8 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0194] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having resonance (ppm) values ​​of 49.2, 54.7, 112.6, and 132.8 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0195] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, which has a resonance (ppm) value comprising the following 13 Solid-state NMR spectra: 54.7 and 112.6 ppm ± 0.2 ppm; and one or both resonance (ppm) values ​​selected from the group consisting of 49.2 and 132.8 ppm ± 0.2 ppm.

[0196] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, which has a resonance (ppm) value comprising the following 13C solid-state NMR spectrum: 54.7 ppm ± 0.2 ppm; and one, two, or three resonance (ppm) values ​​selected from the group consisting of 49.2, 112.6, and 132.8 ppm ± 0.2 ppm.

[0197] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having one, two, three, four, five, or more than five resonance (ppm) values ​​comprising: (a) one, two, three, four, five, or more of the groups selected from Table 12 of values ​​(in ppm ± 0.2 ppm); or (b) with Figure 15 The resonance (ppm) values ​​are basically the same. 13 C solid-state NMR spectrum (ppm).

[0198] In another aspect, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, which is obtained by... 19 Solid-state NMR spectroscopy characterization.

[0199] In one embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having a resonance (ppm) value of -132.4 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0200] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having a resonance (ppm) value of -131.1 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0201] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having resonance (ppm) values ​​comprising -131.1 and -132.4 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0202] In another embodiment, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, having one or two resonance (ppm) values ​​comprising: (a) one or two values ​​selected from the group consisting of values ​​(ppm ± 0.2ppm) in Table 13; or (b) with Figure 16 The resonance (ppm) values ​​shown are essentially the same. 19 F solid-state NMR spectrum (ppm).

[0203] In another aspect, the present invention provides an anhydrous crystalline form (form 6) of PF-07220060, which has:

[0204] (1) Powder X-ray diffraction (PXRD) pattern of peaks at the following 2θ values:

[0205] (a) 6.8 and 10.1°2θ±0.2°2θ;

[0206] (b) 6.8, 10.1 and 12.2°2θ ± 0.2°2θ;

[0207] (c) 6.8, 10.1 and 17.8°2θ±0.2°2θ;

[0208] (d) 6.8, 10.1, 12.2 and 17.8°2θ±0.2°2θ;

[0209] (e) 8.5, 10.1, and 13.8°2θ ± 0.2°2θ;

[0210] (f) 6.8, 8.5 and 13.8°2θ ± 0.2°2θ;

[0211] (g) 6.8, 8.5, 10.1 and 13.8°2θ±0.2°2θ; or

[0212] (h)6.8, 8.5, 10.1, 12.2 and 13.8°2θ±0.2°2θ;

[0213] (2) Includes the following wavenumbers (cm) -1 Raman spectra of values:

[0214] (a) 1436 and 1566 cm -1 ±2cm -1 ;

[0215] (b) 1436 and 1465 cm -1 ±2cm -1 ;or

[0216] (c) 1436, 1465 and 1566 cm -1 ±2cm -1 ;

[0217] (3) Includes the following resonance (ppm) values 13 C solid-state NMR spectrum:

[0218] (a) 54.7 and 112.6 ppm ± 0.2 ppm;

[0219] (b) 54.7 and 132.8 ppm ± 0.2 ppm;

[0220] (c) 112.6 and 132.8 ppm ± 0.2 ppm;

[0221] (d) 54.7, 112.6 and 132.8 ppm ± 0.2 ppm;

[0222] (e) 49.2, 54.7 and 112.6 ppm ± 0.2 ppm;

[0223] (f) 49.2, 54.7 and 132.8 ppm ± 0.2 ppm; or

[0224] (g) 49.2, 54.7, 112.6 and 132.8 ppm ± 0.2 ppm;

[0225] or

[0226] (4) Includes the following resonance (ppm) values 19 F solid-state NMR spectrum:

[0227] (a) -132.4ppm ± 0.2ppm;

[0228] (b) -131.1ppm ± 0.2ppm; or

[0229] (c) -131.1 and -132.4 ppm ± 0.2 ppm;

[0230] Or any combination of two or more of (1)(a) to (h), (2)(a) to (c), (3)(a) to (g) and (4)(a) to (c).

[0231] In another aspect, the present invention provides a pharmaceutical composition comprising an anhydrous crystalline form (form 6) of PF-07220060 according to the aspects or embodiments described herein, and a pharmaceutically acceptable carrier or excipient.

[0232] In another aspect, the present invention provides a method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of anhydrous crystalline form (Form 6) of PF-07220060, or a pharmaceutical composition comprising anhydrous crystalline form (Form 6) of PF-07220060 according to the aspects or embodiments described herein.

[0233] In another aspect, the present invention provides a method for treating cancer in a subject in need, comprising administering to the subject an amount of anhydrous crystalline form of PF-07220060 (Form 6), or a pharmaceutical composition comprising anhydrous crystalline form of PF-07220060 (Form 6) according to the aspects or embodiments described herein and an amount of additional anticancer agent, wherein the amount of anhydrous crystalline PF-07220060 (Form 6) and the additional anticancer agent together is effective in treating cancer.

[0234] In another aspect, the present invention provides the use of an anhydrous crystalline form (Form 6) of PF-07220060, or a pharmaceutical composition comprising an anhydrous crystalline form (Form 6) of PF-07220060 according to the aspects or embodiments described herein, for the treatment of cancer.

[0235] In yet another aspect, the present invention provides the use of the anhydrous crystalline form (form 6) of PF-07220060 according to the aspects or embodiments described herein in the preparation of a medicament for treating cancer.

[0236] In another aspect, the present invention provides an anhydrous crystalline form (Form 6) of PF-07220060 or a pharmaceutical composition comprising an anhydrous crystalline form (Form 6) of PF-07220060 according to the aspects or embodiments described herein, for the treatment of cancer.

[0237] In each aspect and embodiment of the anhydrous crystalline PF-07220060 (Form 6) described herein, the crystalline form may be a substantially pure anhydrous crystalline form of PF-07220060 (Form 6).

[0238] Each embodiment described herein for anhydrous crystallization PF-07220060 (Form 6) may be combined with other such embodiments, provided that these embodiments do not contradict each other.

[0239] In one aspect, the present invention provides an anhydrous crystalline form (form 11) of PF-07220060. In some embodiments, the anhydrous crystalline form (form 11) of PF-07220060 is characterized by its powder X-ray diffraction (PXRD) pattern. In one embodiment, the present invention provides an anhydrous crystalline form (form 11) of PF-07220060, which has a composition containing... Figure 17 PXRD plots of peaks at essentially the same 2θ values.

[0240] In another aspect, the present invention provides a pharmaceutical composition comprising an anhydrous crystalline form (form 11) of PF-07220060 according to the aspects or embodiments described herein, and a pharmaceutically acceptable carrier or excipient.

[0241] In another aspect, the present invention provides a method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of anhydrous crystalline form (Form 11) of PF-07220060, or a pharmaceutical composition comprising anhydrous crystalline form (Form 11) of PF-07220060 according to the aspects or embodiments described herein.

[0242] In another aspect, the present invention provides a method for treating cancer in a subject in need, comprising administering to the subject an amount of anhydrous crystalline form of PF-07220060 (Form 11), or a pharmaceutical composition comprising anhydrous crystalline form of PF-07220060 (Form 11) according to the aspects or embodiments described herein and an amount of additional anticancer agent, wherein the amount of anhydrous crystalline PF-07220060 (Form 11) and the additional anticancer agent together is effective in treating cancer.

[0243] In another aspect, the present invention provides the use of an anhydrous crystalline form (Form 11) of PF-07220060, or a pharmaceutical composition comprising an anhydrous crystalline form (Form 11) of PF-07220060 according to the aspects or embodiments described herein, for the treatment of cancer.

[0244] In yet another aspect, the present invention provides the use of the anhydrous crystalline form (form 11) of PF-07220060 according to the aspects or embodiments described herein in the preparation of a medicament for treating cancer.

[0245] In another aspect, the present invention provides an anhydrous crystalline form (Form 11) of PF-07220060 or a pharmaceutical composition comprising an anhydrous crystalline form (Form 11) of PF-07220060 according to the aspects or embodiments described herein, for the treatment of cancer.

[0246] In each aspect and embodiment of the anhydrous crystalline PF-07220060 (Form 11) described herein, the crystalline form may be a substantially pure anhydrous crystalline form (Form 11) of PF-07220060.

[0247] Each embodiment described herein for anhydrous crystallization PF-07220060 (Form 11) may be combined with other such embodiments, provided that these embodiments do not contradict each other.

[0248] In some embodiments of the methods and uses described herein, the cancer is selected from the group consisting of: breast cancer, prostate cancer, lung cancer (including non-small cell lung cancer, NSCLC, and small cell lung cancer SCLC), liver cancer (including hepatocellular carcinoma HCC), kidney cancer (including renal cell carcinoma RCC), bladder cancer (including urothelial carcinoma, such as upper urinary tract urothelial carcinoma UUTUC), ovarian cancer (including epithelial ovarian cancer EOC), peritoneal cancer (including primary peritoneal carcinoma PPC), fallopian tube cancer, cervical cancer, uterine cancer (including endometrial cancer), pancreatic cancer, gastric cancer, colorectal cancer, esophageal cancer, head and neck cancer (including squamous cell carcinoma of the head and neck (SCCHN), thyroid cancer, and salivary gland cancer), testicular cancer, adrenal cancer, skin cancer (including basal cell carcinoma and melanoma), brain cancer (including astrocytoma, meningioma, and glioblastoma), sarcoma (including osteosarcoma and liposarcoma), and lymphoma (including mantle cell lymphoma MCL).

[0249] In some embodiments of the methods and uses described herein, the cancer is advanced or metastatic. In some embodiments of the methods and uses described herein, the cancer is early or non-metastatic.

[0250] In some embodiments of the methods and uses described herein, the cancer is characterized by amplification or overexpression of CDK4, CDK6, and / or cyclin D1 (CCND1). In some embodiments, the cancer is RB-positive or RB-proficient.

[0251] In some embodiments of the methods and uses described herein, the cancer is resistant to a class of therapeutic agents or pharmaceuticals, such as standard care agents or classes for a particular cancer. In some embodiments of the methods and uses described herein, the cancer is characterized by innate or acquired resistance to a class of therapeutic agents or pharmaceuticals. In some such embodiments, the cancer is resistant to treatment using antiandrogens, taxanes, platinum-based agents, aromatase inhibitors, selective estrogen receptor degraders (SERDs), selective estrogen receptor modulators (SERMs), or CDK4 / 6 inhibitors.

[0252] In some embodiments of the methods and uses described herein, the cancer is breast cancer. In some such embodiments, the breast cancer is androgen-dependent breast cancer. In some embodiments, the breast cancer is AR+ breast cancer.

[0253] In some embodiments of the methods and uses described herein, the breast cancer is advanced or metastatic breast cancer. In some embodiments of the methods and uses described herein, the breast cancer is early or non-metastatic breast cancer.

[0254] In some embodiments of the methods and uses described herein, the breast cancer is characterized by amplification or overexpression of CDK4, CDK6, and / or cyclin D1 (CCND1). In some embodiments, the breast cancer is characterized as RB-positive, RB-intact, or RB-wild.

[0255] In some embodiments of the methods and uses described herein, the breast cancer is a BRCA1- or BRCA2-mutated breast cancer.

[0256] In some embodiments of the methods and uses described herein, the breast cancer is a PIK3CA-mutated breast cancer.

[0257] In some embodiments of the methods and uses described herein, the breast cancer is refractory to or resistant to treatment with one or more standard care agents, or has progressed with one or more standard care agents. In some such embodiments, the breast cancer is refractory to or resistant to treatment with anti-estrogens (such as aromatase inhibitors, SERDs, or SERMs), or has progressed with anti-estrogens (such as aromatase inhibitors, SERDs, or SERMs). In some such embodiments, the breast cancer is refractory to or resistant to treatment with CDK4 / 6 inhibitors (such as palbociclib or a pharmaceutically acceptable salt thereof), or has progressed with CDK4 / 6 inhibitors (such as palbociclib or a pharmaceutically acceptable salt thereof). In other embodiments, the breast cancer is refractory to or resistant to treatment with antitumor chemotherapeutic agents (such as taxanes, platinum agents, anthracyclines, or antimetabolites), or has progressed with treatment with such agents.

[0258] In some embodiments of the methods and uses described herein, the breast cancer is hormone receptor (HR) positive (HR+) breast cancer, that is, the breast cancer is estrogen receptor (ER) positive (ER+) and / or progesterone receptor (PR) positive (PR+).

[0259] In some implementations, the breast cancer is hormone receptor (HR) negative (HR-), that is, the breast cancer is estrogen receptor (ER) negative (ER-) and progesterone receptor (PR) negative (PR-).

[0260] In some implementations, the breast cancer is human epidermal growth factor receptor 2 (HER2) positive (HER2+).

[0261] In some embodiments, the breast cancer is HER2-negative (HER2-). In some such embodiments, the breast cancer is ERα-negative (ERα).

[0262] In some implementations, the breast cancer is triple-negative breast cancer (TNBC), that is, the breast cancer is ER-, PR-, and HER2-.

[0263] In some embodiments, the breast cancer is selected from the group consisting of HR+ / HER2- breast cancer, HR+ / HER2+ breast cancer, HR- / HER2+ breast cancer, and triple-negative breast cancer (TNBC). In some such embodiments, the breast cancer is androgen-dependent or AR+ breast cancer. In some such embodiments, the breast cancer is BRCA1- or BRCA2-mutated breast cancer.

[0264] In some embodiments, the breast cancer is HR+ / HER2- breast cancer. In some such embodiments, the HR+ / HER2- breast cancer is advanced or metastatic HR+ / HER2- breast cancer. In some embodiments, the HR+ / HER2- breast cancer is early or non-metastatic HR+ / HER2- breast cancer.

[0265] In some embodiments, the HR+ / HER2- breast cancer is characterized by amplification or overexpression of CDK4, CDK6, and / or cyclin D1 (CCND1). In some embodiments, the HR+ / HER2- breast cancer is characterized as RB-positive, RB-intact, or RB-wild-type.

[0266] In some implementations, the HR+ / HER2- breast cancer is a breast cancer with a BRCA1- or BRCA2- mutation.

[0267] In some implementations, this HR+ / HER2- breast cancer is a PIK3CA-mutated breast cancer.

[0268] In some such embodiments, the HR+ / HER2- breast cancer is refractory or resistant to treatment with standard care agents (e.g., anti-estrogens, such as aromatase inhibitors, SERDs, or SERMs), or has progressed under standard care agents (e.g., anti-estrogens, such as aromatase inhibitors, SERDs, or SERMs). In some such embodiments, the HR+ / HER2- breast cancer is refractory or resistant to treatment with CDK4 / 6 inhibitors (such as palbociclib or a pharmaceutically acceptable salt thereof), or has progressed under CDK4 / 6 inhibitors (such as palbociclib or a pharmaceutically acceptable salt thereof).

[0269] In some such embodiments, the HR+ / HER2- breast cancer is refractory or resistant to anti-estrogen therapy (such as aromatase inhibitors, SERD, or SERM). In some such embodiments, the HR+ / HER2- breast cancer is refractory or resistant to treatment with CDK4 / 6 inhibitors (such as palbociclib or a pharmaceutically acceptable salt thereof). In some such embodiments, the HR+ / HER2- breast cancer is refractory or resistant to treatment with CDK4 / 6 inhibitors (such as palbociclib or a pharmaceutically acceptable salt thereof) in combination with an anti-estrogen agent (such as letrozole or fulvestrant).

[0270] In some such embodiments, the HR+ / HER2- breast cancer is resistant to treatment with anti-estrogen agents (such as aromatase inhibitors, SERD, or SERM). In some such embodiments, the HR+ / HER2- breast cancer is resistant to treatment with CDK4 / 6 inhibitors (such as palbociclib or a pharmaceutically acceptable salt thereof). In some such embodiments, the HR+ / HER2- breast cancer is resistant to further combination therapy with CDK4 / 6 inhibitors (such as palbociclib or a pharmaceutically acceptable salt thereof) and anti-estrogen agents (such as letrozole or fulvestrant).

[0271] In some implementations, the breast cancer is HR+ / HER2+ breast cancer. In some implementations, the breast cancer is HR- / HER2+ breast cancer.

[0272] In some embodiments where the breast cancer is HR+, the methods and uses described herein further include an additional anticancer agent. In some such embodiments, the additional anticancer agent is an anti-estrogen agent, such as an aromatase inhibitor, SERD, or SERM. In some such embodiments, the anti-estrogen agent is letrozole or fulvestrant. In some such embodiments, the additional anticancer agent is a CDK4 / 6 inhibitor, such as palbociclib or a pharmaceutically acceptable salt thereof. In some such embodiments, the additional anticancer agent, a CDK4 / 6 inhibitor (such as palbociclib or a pharmaceutically acceptable salt thereof), is further combined with an anti-estrogen agent (e.g., letrozole or fulvestrant). In some such embodiments, the additional anticancer agent is a PI3K inhibitor, such as alpelisib.

[0273] In some embodiments of HER2+ breast cancer, the methods and uses described herein further include additional anticancer agents. In some such embodiments, the additional anticancer agent is a HER2-targeting agent, such as trastuzumab emtansine, fam-trastuzumab deruxtecan, pertuzumab, lapatinib, neratinib, or tucatinib, or an agent targeting the PI3K / AKT / mTOR molecular pathway, such as ipatasertib.

[0274] In some embodiments, the breast cancer is triple-negative breast cancer (TNBC). In some embodiments, the TNBC is androgen-dependent or AR+ TNBC. In some such embodiments, the TNBC is RN+ or RB-proficient. In some such embodiments, the TNBC is AR+, RB+, or AR+, RB-proficient TNBC.

[0275] In some such embodiments, the TNBC is locally recurrent / advanced or metastatic TNBC. In some such embodiments, the TNBC is advanced or metastatic TNBC. In some such embodiments, the TNBC is early or non-metastatic TNBC.

[0276] In some implementations, the TNBC is characterized by the amplification or overexpression of CDK4, CDK6, and / or cyclin D1 (CCND1).

[0277] In some implementations, the TNBC is a BRCA1- or BRCA2- mutated TNBC.

[0278] In some implementations, the TNBC is refractory or resistant to standard care agents (such as antitumor chemotherapy agents, such as taxanes, platinum agents, anthracyclines, or antimetabolites), or has progressed under their treatment.

[0279] In some embodiments of the methods and uses described herein, the cancer is prostate cancer. In some such embodiments, the prostate cancer is androgen-dependent. In some such embodiments, the prostate cancer is AR+ prostate cancer.

[0280] In some embodiments of the methods and uses described herein, the prostate cancer is advanced or metastatic prostate cancer. In some embodiments of the methods and uses described herein, the prostate cancer is early or non-metastatic prostate cancer. In some embodiments of the methods and uses described herein, the prostate cancer is BRCA1- or BRCA2-mutated prostate cancer.

[0281] In some embodiments, the prostate cancer is castration-resistant prostate cancer. In other embodiments, the prostate cancer is castration-sensitive prostate cancer. In some embodiments of the methods and uses described herein, the prostate cancer is metastatic prostate cancer (mPC). In some such embodiments, the mPC is metastatic castration-resistant prostate cancer (mCRPC). In other such embodiments, the mPC is metastatic castration-sensitive prostate cancer (mCSPC). In some embodiments of the methods and uses described herein, the prostate cancer is non-metastatic prostate cancer (nmPC). In some such embodiments, the nmPC is non-metastatic castration-resistant prostate cancer (nmCRPC). In some such embodiments, the nmPC is non-metastatic castration-sensitive prostate cancer (nmCSPC).

[0282] In some embodiments of the methods and uses described herein, the prostate cancer is refractory or resistant to treatment with one or more standard care agents, or has progressed under one or more standard care agents. In some such embodiments, the prostate cancer is refractory or resistant to treatment with antiandrogen therapy, or has progressed under antiandrogen therapy. In other embodiments, the prostate cancer is refractory or resistant to treatment with antitumor chemotherapeutic agents (such as taxanes, platinum agents, anthracyclines, or antimetabolites), or has progressed under antitumor chemotherapeutic agents (such as taxanes, platinum agents, anthracyclines, or antimetabolites).

[0283] In some such implementations, the prostate cancer is refractory to or resistant to treatment with anti-androgen agents.

[0284] In some embodiments of the methods and uses described herein, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some such embodiments, the lung cancer is advanced or metastatic lung cancer.

[0285] In some embodiments of the methods and uses described herein, the cancer is liver cancer. In some such embodiments, the liver cancer is hepatocellular carcinoma (HCC). In some such embodiments, the liver cancer is advanced or metastatic liver cancer.

[0286] In some embodiments of the methods and uses described herein, the cancer is kidney cancer. In some such embodiments, the kidney cancer is renal cell carcinoma (RCC). In some such embodiments, the kidney cancer is advanced or metastatic kidney cancer.

[0287] In some embodiments of the methods and uses described herein, the cancer is bladder cancer. In some such embodiments, the bladder cancer is urothelial carcinoma, including upper urinary tract urothelial carcinoma (UUTUC). In some such embodiments, the bladder cancer is advanced or metastatic bladder cancer.

[0288] In some embodiments of the methods and uses described herein, the cancer is ovarian cancer, including epithelial ovarian cancer (EOC). In some such embodiments, the ovarian cancer is advanced or metastatic ovarian cancer.

[0289] In some embodiments of the methods and uses described herein, the cancer is peritoneal cancer, including primary peritoneal cancer (PPC). In some such embodiments, the peritoneal cancer is advanced or metastatic peritoneal cancer.

[0290] In some embodiments of the methods and uses described herein, the cancer is fallopian tube cancer. In some such embodiments, the fallopian tube cancer is advanced or metastatic fallopian tube cancer.

[0291] In some embodiments of the methods and uses described herein, the cancer is cervical cancer. In some such embodiments, the cervical cancer is advanced or metastatic cervical cancer.

[0292] In some embodiments of the methods and uses described herein, the cancer is uterine cancer, including endometrial cancer. In some such embodiments, the uterine cancer is advanced or metastatic uterine cancer.

[0293] In some embodiments of the methods and uses described herein, the cancer is pancreatic cancer. In some such embodiments, the pancreatic cancer is advanced or metastatic pancreatic cancer. In some such embodiments, the pancreatic cancer is resistant to antitumor chemotherapeutic agents (such as taxanes, platinum agents, anthracyclines, or antimetabolites). In some such embodiments, the pancreatic cancer is resistant to gemcitabine or nab-paclitaxel.

[0294] In some embodiments of the methods and uses described herein, the cancer is gastric cancer. In some such embodiments, the gastric cancer is advanced or metastatic gastric cancer.

[0295] In some embodiments of the methods and uses described herein, the cancer is colorectal cancer. In some such embodiments, the colorectal cancer is advanced or metastatic colorectal cancer.

[0296] In some embodiments of the methods and uses described herein, the cancer is esophageal cancer. In some such embodiments, the esophageal cancer is advanced or metastatic esophageal cancer.

[0297] In some embodiments of the methods and uses described herein, the cancer is head and neck cancer. In some such embodiments, the head and neck cancer is advanced or metastatic head and neck cancer. In some such embodiments, the head and neck cancer is squamous cell carcinoma of the head and neck (SCCHN), thyroid cancer, or salivary gland cancer. In some such embodiments, the head and neck cancer is salivary gland cancer.

[0298] In some embodiments of the methods and uses described herein, the cancer is testicular cancer. In some such embodiments, the testicular cancer is advanced or metastatic testicular cancer.

[0299] In some embodiments of the methods and uses described herein, the cancer is adrenal carcinoma. In some such embodiments, the adrenal carcinoma is advanced or metastatic adrenal carcinoma.

[0300] In some embodiments of the methods and uses described herein, the cancer is skin cancer. In some such embodiments, the skin cancer is basal cell carcinoma or melanoma. In some such embodiments, the skin cancer is advanced or metastatic skin cancer.

[0301] In some embodiments of the methods and uses described herein, the cancer is brain cancer. In some such embodiments, the brain cancer is astrocytoma, meningioma, or glioblastoma. In some such embodiments, the brain cancer is advanced or metastatic brain cancer.

[0302] In some embodiments of the methods and uses described herein, the cancer is a sarcoma. In some such embodiments, the sarcoma is osteosarcoma or liposarcoma.

[0303] In some embodiments of the methods and uses described herein, the cancer is lymphoma. In some such embodiments, the lymphoma is mantle cell lymphoma (MCL).

[0304] In some embodiments, the compounds of the present invention are administered as first-line therapy. In other embodiments, the compounds of the present invention are administered as second-line (or subsequent) therapy.

[0305] In some embodiments, the compounds of the present invention are administered as second-line (or subsequent) therapy after treatment with endocrine therapy agents and / or CDK4 / CDK6 inhibitors. In some embodiments, the compounds of the present invention are administered as second-line (or subsequent) therapy after treatment with endocrine therapy agents (e.g., aromatase inhibitors, SERMs, or SERDs). In some embodiments, the compounds of the present invention are administered as second-line (or subsequent) therapy after treatment with CDK4 / 6 inhibitors. In some embodiments, the compounds of the present invention are administered as second-line (or subsequent) therapy after treatment with one or more chemotherapy regimens (e.g., those containing taxanes or platinum). In some embodiments, the compounds of the present invention are administered as second-line (or subsequent) therapy after treatment with an anti-HER2 targeting agent (e.g., trastuzumab).

[0306] As used herein, an “effective dose,” “effective amount,” or “therapeutic effective amount” of a compound or pharmaceutical composition is an amount sufficient to affect one or more beneficial or desired outcomes when used as directed (either alone if used as a single agent, or together with other agents if used in combination), including the prevention, improvement, or treatment of a disease, its complications, and biochemical, histological, or behavioral symptoms of an intermediate pathological phenotype presented during disease development. For prophylactic use, beneficial or desired outcomes may include: eliminating or reducing risk, reducing severity, or delaying the onset of disease. For therapeutic use, beneficial or desired outcomes may include: reducing morbidity or improving one or more symptoms of the disease, reducing the dose of another drug used to treat the disease, enhancing the efficacy or safety of another drug used to treat the disease, or delaying the time of disease progression.

[0307] When referring to cancer treatment, the therapeutically effective dose refers to a dose that has the following effects: (1) reducing the size of the tumor, (2) inhibiting (i.e., slowing down, preferably stopping) tumor metastasis, (3) inhibiting (i.e., slowing down, preferably stopping) tumor growth or tumor infiltration to some extent, (4) alleviating (or preferably eliminating) one or more signs or symptoms associated with cancer to some extent, (5) reducing the dosage of other drugs required to treat the disease, and / or (6) enhancing the effect of another drug, and / or (7) delaying the progression of the patient's disease.

[0308] An effective dose may be administered once or multiple times. For the purposes of this invention, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventative or therapeutic treatment. As understood in a clinical context, an effective dose of a drug, compound, or pharmaceutical composition may be achieved with or without combination with another drug, compound, or pharmaceutical composition.

[0309] A “non-standard dosing regimen” refers to a regimen for administering a substance, drug, compound, or pharmaceutical composition in a manner that differs from the amount, dose, or schedule of the substance, drug, compound, or pharmaceutical composition typically used in clinical or therapeutic settings. A “non-standard dosing regimen” may include a “non-standard dose” or a “non-standard dosing schedule.”

[0310] A “low-dose regimen” refers to a dosing regimen in which one or more of the substances, agents, compounds, or pharmaceutical compositions in the regimen are administered in a lower amount or dose than is typically used for that agent in a clinical or therapeutic setting (e.g., when the agent is administered as a single-agent therapy).

[0311] The retinoblastoma susceptibility gene (RB1) is the first tumor suppressor gene to be molecularly defined. The retinoblastoma gene product RB is frequently mutated or deleted in retinoblastoma and osteosarcoma, and is mutated or deleted at variable frequencies in other tumor types, such as prostate cancer (including neuroendocrine prostate cancer), breast cancer (including triple-negative breast cancer TNBC), lung cancer (including small cell lung cancer SCLC and non-small cell lung cancer NSCLC), liver cancer, bladder cancer, ovarian cancer, uterine cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, glioblastoma, and lymphoma. In human cancers, the function of RB can be disrupted by neutralization by bound proteins (e.g., human papillomavirus-E7 protein in cervical cancer; Ishiji, T, 2000, J Dermatol., 27:73-86) or by dysregulation of pathways ultimately responsible for its phosphorylation.

[0312] The “RB pathway” refers to the entire molecular signaling pathway that includes retinoblastoma protein (RB) and other protein / protein families, including (but not limited to) CDK, E2f, atypical protein kinase C, and Skp2. Inactivation of the RB pathway is typically caused by disturbances of p16INK4a, cyclin D1, and CDK4.

[0313] The terms “RB+”, “RB plus”, “RB healthy”, or “RB positive” are used to describe cells expressing detectable amounts of functional RB proteins. RB positivity includes wild-type and unmutated RB proteins. Wild-type RB (RB-WT) should generally be understood as referring to the form of the RB protein that is normally present in the corresponding population and has the function currently assigned to this protein. RB positive cells can be cells containing functional RB genes. RB positive cells can also be cells that encode detectable RB protein function.

[0314] The terms “RB-”, “RB-reduced”, “RB-deficient”, or “RB-negative” describe several types of cells in which the function of RB is impaired, including cells that produce undetectable amounts of functional RB proteins. RB-negative cells can be cells that do not contain functional RB genes. RB-negative cells can also be cells that encode RB proteins, but in which the protein functions improperly.

[0315] In some embodiments of the methods and uses described herein, the cancer is characterized as retinoblastoma wild-type (RB-WT). In some embodiments of the methods and uses described herein, the cancer is characterized as RB-positive or RB-benign. Such RB-positive or RB-benign cancers contain at least some functional retinoblastoma genes. In some embodiments, such RB-WT, RB-positive, or RB-benign cancers are characterized as RB1-WT, RB1-positive, or RB1-benign cancers.

[0316] In some embodiments of the methods and uses described herein, the cancer is characterized as RB-negative or RB-deficient. Such RB-negative or RB-deficient cancers can be characterized by loss-of-function mutations that encode missense mutations (i.e., encoding incorrect amino acids) or nonsense mutations (i.e., encoding stop codons). Alternatively, such RB-negative cancers can be characterized by the deletion of all or part of the retinoblastoma gene. In some embodiments, such RB-negative or RB-deficient cancers are characterized as RB1-negative or RB1-deficient.

[0317] When the term "tumor" is used to describe a subject diagnosed with or suspected of having cancer, it refers to any malignant or potentially malignant growth or mass of tissue of any size, including both primary and secondary growths. A solid tumor is an abnormal growth or mass of tissue that does not typically contain cysts or fluid-filled areas. Examples of solid tumors include sarcomas, carcinomas, and lymphomas. Leukemia (blood cancer) generally does not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

[0318] "Tumor burden" or "tumor load" refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor throughout the body (including lymph nodes and bone marrow). Tumor burden can be measured by various methods known in the art, such as, for example, using calipers, or, when in vivo, using imaging techniques such as ultrasound, bone scan, computed tomography (CT), or magnetic resonance imaging (MRI).

[0319] The term "tumor size" refers to the total size of a tumor that can be measured as its length and width. Tumor size can be determined by various methods known in the art, such as, for example, by measuring the size of the tumor after removal from the subject, for example, using calipers, or when in vivo, using imaging techniques, such as bone scans, ultrasound, CR, or MRI scans.

[0320] The terms "patient" or "subject" refer to any individual subject who requires treatment or is participating in a clinical trial, epidemiological study, or serving as a control, including human and mammalian veterinary patients (such as cattle, horses, dogs, and cats). In some implementations, the subject is a human.

[0321] In some embodiments of the methods and uses described herein, the patient or subject is an adult. In some embodiments, the subject is a woman or man of any menopausal state. In some embodiments, the subject is a postmenopausal woman or man. In some embodiments, the subject is a postmenopausal woman. In some embodiments, the subject is a premenopausal or perimenopausal woman. In some embodiments, the subject is a premenopausal or perimenopausal woman treated with a luteinizing hormone-releasing hormone (LHRH) agonist. In some such embodiments, the subject is a man. In some embodiments, the subject is a man treated with an LHRH or gonadotropin-releasing hormone (GnRH) agonist.

[0322] As used herein, the term "treat / treating" in cancer refers to administering the compounds of the present invention to a subject who has cancer or has been diagnosed with cancer to achieve at least one positive therapeutic effect, such as, for example, reducing the number of cancer cells, reducing tumor size, reducing the rate at which cancer cells infiltrate surrounding organs, or reducing the rate of tumor metastasis or tumor growth, reversing, alleviating, or inhibiting the progression of the condition or symptom to which this term applies, or one or more symptoms of the condition or symptom to which this term applies, or preventing or delaying the recurrence of the condition or symptom to which this term applies, or one or more symptoms of the condition or symptom to which this term applies. As used herein, unless otherwise specified, the term "treat" means a therapeutic action as defined above. The term "treat" also includes adjuvant and neoadjuvant treatments for the subject, such as after surgery or radiation therapy.

[0323] For the purposes of this invention, beneficial or desired clinical outcomes include (but are not limited to) one or more of the following: reduction of the proliferation of neoplasms or cancer cells (or destruction of neoplasms or cancer cells); inhibition of metastases or neoplasms; reduction or shrinkage of tumor size; cancer relief; reduction of symptoms caused by cancer; improvement of the quality of life of those with cancer; reduction of the dosage of other drugs required to treat cancer; delay of cancer progression; cure of cancer; overcoming one or more drug resistance mechanisms of cancer; and / or prolongation of survival in cancer patients. The positive therapeutic effect on cancer can be measured by several methods (see, for example, W.A. Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Supplement 1:1S-10S (2009)). For example, regarding tumor growth inhibition (T / C), according to the National Cancer Institute (NCI) criteria, a T / C less than or equal to 42% is considered the minimum level of antitumor activity. A T / C <10% is considered a high level of antitumor activity, where T / C (%) = median treated tumor volume / median control tumor volume x 100.

[0324] In some embodiments, the treatment achieved by the compounds of the present invention is defined with reference to any of the following: partial response (PR), complete response (CR), overall response (OR), objective rate of response (ORR), progression-free survival (PFS), radiographic PFS, metastasis-free survival (MFS), disease-free survival (DFS), and overall survival (OS).

[0325] As used in this article, the terms "complete response" or "CR" mean that all signs of cancer disappear in response to treatment (e.g., disappearance of all target lesions). This does not always mean that the cancer has been cured.

[0326] As used in this article, the term “disease-free survival” (DFS) refers to the length of time a patient survives without any signs or symptoms of the cancer after the initial treatment for the cancer has ended.

[0327] As used in this article, the term “duration of response” (DoR) refers to the length of time a tumor continues to respond to treatment without cancer growth or spread. Treatments that demonstrate an improved DoR can produce a durable, meaningful delay in disease progression.

[0328] As used herein, the terms “objective response” and “overall response” refer to a measurable response, including complete response (CR) or partial response (PR). The term “overall response rate” (ORR) refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0329] As used in this article, the term “overall survival” (OS) refers to the length of time a patient diagnosed with a disease (such as cancer) is still alive from the date of diagnosis or the start of treatment. OS is typically measured as the extension of life expectancy of patients receiving a specific treatment compared to patients in a control group (i.e., those taking another drug or a placebo).

[0330] As used herein, the term “partial response” or “PR” refers to a reduction in the size of one or more tumors or lesions, or the extent of cancer in the body, in response to treatment. For example, in some implementations, PR refers to a reduction of at least 30% in the sum of the longest diameters (SLD) of the targeted lesions, with reference to baseline SLD.

[0331] As used in this article, the term “progression-free survival” or “PFS” refers to the length of time during and after treatment when the disease being treated (e.g., cancer) does not worsen. PFS, also known as “time to tumor progression,” can include the amount of time for patients who have achieved CR or PR, as well as the amount of time for patients who have achieved SD.

[0332] As used herein, the term "progressive disease" or "PD" refers to cancer that is growing, spreading, or becoming more severe. In some implementations, PR refers to an increase of at least 20% in the target lesion's SLD, with reference to the minimum SLD recorded from the start of treatment, or to the presence of one or more new lesions.

[0333] As used in this article, the term “stable disease” (SD) refers to cancer whose degree or severity neither decreases nor increases.

[0334] As used herein, the term "sustained response" refers to a sustained effect on reducing tumor growth after treatment has been discontinued. For example, the tumor size may be the same as or smaller than its size at the start of drug administration. In some embodiments, the sustained response has a duration at least equal to, and at least 1.5, 2, 2.5, or 3 times longer than, the duration of treatment.

[0335] As used in this article, the anticancer effects of cancer treatments, including “objective response,” “complete response,” “partial response,” “progressive disease,” “stable disease,” “progression-free survival,” and “duration of response,” can be defined and assessed by researchers using RECIST v1.1 (Eisenhauer et al., New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1), Eur J of Cancer, 2009; 45(2):228-47).

[0336] In some embodiments of the methods and uses described herein, the present invention relates to neoadjuvant therapy, adjuvant therapy, first-line therapy, second-line therapy, second- or later-line therapy, or third- or later-line therapy. In the various cases further described herein, the cancer may be localized, advanced, or metastatic, and the invention may occur at any point in time along the disease continuum (i.e., at any stage of the cancer).

[0337] Treatment regimens of the compounds of the present invention that are effective in treating cancer patients may vary depending on factors such as disease stage, patient age and weight, and the ability of the therapy to elicit an anticancer response in the subject. While embodiments of any aspect of the invention may not effectively achieve a positive therapeutic effect in every subject, a positive therapeutic effect should be achieved in a statistically significant number of subjects, as determined by any statistical test known in the art, such as Student's t-test, chi2 test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test.

[0338] The terms “treatment regimen,” “dosing protocol,” and “dosing regimen” are used interchangeably to refer to the dosage and timing of administration, alone or in combination with another anticancer agent, of the crystalline or amorphous form of PF-07220060 as described herein, or of a pharmaceutical composition comprising the crystalline or amorphous form of PF-07220060. In a preferred embodiment, the treatment regimen refers to crystalline PF-07220060 monohydrate (Form 2). In some embodiments, the treatment regimen refers to anhydrous crystalline PF-07220060 (Form 6), anhydrous crystalline PF-07220060 (Form 11), or amorphous PF-07220060 (Form 8). “Improvement” means that, following treatment with a compound or drug, such as the crystalline or amorphous form of PF-07220060 as described herein, or of a pharmaceutical composition comprising the crystalline or amorphous form of PF-07220060, one or more symptoms are reduced or improved to a certain extent compared to the absence of administration of the compound. "Improvement" also includes shortening or reducing the duration of symptoms, that is, reducing to some extent, preferably eliminating symptoms.

[0339] As used herein, unless otherwise specified, “abnormal cell growth” refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth can be benign (non-cancerous) or malignant (cancerous). In a typical implementation of the methods provided herein, the abnormal cell growth is cancerous.

[0340] Abnormal cell growth includes the following abnormal growths: (1) tumors characterized by amplification or overexpression of CDK4, CDK6 and / or cyclin D1 (CCND1); (2) tumors proliferating through abnormal CDK4 activation; and (3) tumors resistant to endocrine therapy, CDK4 and / or CDK6 inhibition, HER2 antagonists, taxanes, platinum, or other standard care agents.

[0341] In some embodiments, the methods and uses of the present invention may further comprise one or more additional anticancer agents. In some embodiments, the additional anticancer agent is selected from the group consisting of antitumor agents, anti-angiogenic agents, signal transduction inhibitors, and antiproliferative agents. In some embodiments, the additional anticancer agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, embedded antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, and endocrine therapeutic agents (such as antiandrogens, androgen deprivation therapy (ADT), and antiestrogens). The additional anticancer agent may include small molecule therapeutic agents and their pharmaceutically acceptable salts or solvates, therapeutic antibodies, antibody-drug conjugates (ADCs), protein hydrolysis-targeting chimeras, or antisense molecules.

[0342] In some embodiments, the additional anticancer agent is an anti-estrogenic agent, wherein the anti-estrogenic agent is an aromatase inhibitor, SERD, or SERM. In some embodiments, the anti-estrogenic agent is an aromatase inhibitor. In some such embodiments, the aromatase inhibitor is selected from the group consisting of letrozole, anastrozole, and exemestane. In some such embodiments, the aromatase inhibitor is letrozole. In some embodiments, the anti-estrogenic agent is a SERD. In some such embodiments, the SERD is selected from the group consisting of: fulvestrant, elacestrant (RAD-1901, Radius Health), SAR439859 (Sanofi), RG6171 (Roche), AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), rintodestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Lilly), and SHR9549 (Jiansu Hengrui Medicine). In some such embodiments, the SERD is fulvestrant. In some embodiments, the anti-estrogenic agent is a SERM. In some such embodiments, the SERM is selected from the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, bazedoxifene, and afimoxifene. In some such embodiments, the SERM is either tamoxifen or raloxifene.

[0343] In some embodiments, the additional anticancer agent is an antiandrogen, such as abiraterone, apalutamide, bicalutamide, cyproterone, enzalutamide, flutamide, or nilutamide. In some embodiments, the method or use further comprises androgen blocking therapy (ADT), such as a luteinizing hormone-releasing hormone (LHRH) agonist, an LHRH antagonist, a gonadotropin-releasing hormone (GnRH) agonist, or a GnRH antagonist.

[0344] In some embodiments, the methods and uses of the present invention further comprise one or more additional anticancer agents selected from the following:

[0345] Anti-angiogenic agents include, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (α-v / β-3), MMP-2 (matrix metalloproteinase 2) inhibitors, and MMP-9 (matrix metalloproteinase 9) inhibitors.

[0346] Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors, serine / threonine kinase inhibitors, or cyclin-dependent kinase inhibitors), protease inhibitors, PI3K / AKT / mTOR pathway inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) inhibitors, B-cell lymphoma 2 (BCL2) inhibitors, neurotrophic protein receptor kinase (NTRK) inhibitors, transfection rearrangement (RET) inhibitors, Notch inhibitors, PARP inhibitors, Hedgehog pathway inhibitors, and selective nuclear export inhibitors (SINE).

[0347] Examples of signal transduction inhibitors include (but are not limited to): acalabrutinib, afatinib, alectinib, alpelisib, axitinib, binimetinib, bortezomib, bosutinib, brigatinib, cabozantinib, carfilzomib, ceritinib, and cobimetinib. Copanlisib, crizotinib, dabrafenib, dacomitinib, dasatinib, duvelisib, enasidenib, encorafenib, entrectinib, erlotinib, gefitinib, gilteritinib, glasdegib, ibrutinib, and others. Delalisib, Imatinib, Ipatasetinib, Ivosidenib, Ixazomib, Lapatinib, Larotrectinib, Lenvatinib, Lorlatinib, Midostaurin, Neratinib, Nilotinib, Niraparib, Olaparib, Osimertinib, Pazopanib The following are pharmaceutically acceptable salts and solvates thereof: ponatinib, regorafenib, rucaparib, ruxolitinib, sonidegib, sorafenib, sunitinib, talazoparib, trametinib, vandetanib, vemurafenib, venetoclax, and vismodegib.

[0348] Antitumor agents include, for example, alkylating agents, platinum coordination complexes, cytotoxic antibiotics, antimetabolites, biological response modifiers, histone deacetylation (HDAC) inhibitors, hormones, monoclonal antibodies, growth factor inhibitors, taxanes, topoisomerase inhibitors, vinca alkaloids, and other agents.

[0349] Alkylating agents include: altretamine, bendamustine, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, procarbazine, streptozocin, temozolomide, thiotepa, and trabectedin.

[0350] Platinum coordination complexes (also referred to in this article as) “ Platinum preparation) Including: carboplatin, cisplatin, and oxaliplatin.

[0351] Cytotoxic antibiotics include: bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, mitoxantrone, plicamycin, and valrubicin.

[0352] Antimetabolites include: antifolates, such as methotrexate, pemetrexed, pralatrexate, and trimetrexate; purine analogs, such as azathioprine, cladribine, fludarabine, mercaptopurine, and thioguanine; and pyrimidine analogs, such as azacitidine, capecitabine, cytarabine, decitabine, fluxuridine, fluorouracil, gemcitabine, and trifluridine / tipracil.

[0353] Biological response modifiers include: aldesleukin (IL-2), denileukin diftitox, and interferon-γ.

[0354] Histone deacetylase inhibitors include belinostat, panobinostat, romidepsin, and vorinostat.

[0355] Hormonal agents include antiandrogens, antiestrogens, gonadotropin-releasing hormone (GnRH) analogs, and peptide hormones. Examples of antiestrogens include: aromatase inhibitors, such as letrozole, anastrozole, and exemestane; SERDs, such as fulvestrant, erastrant (RAD-1901, Radius Health), SAR439859 (Sanofi), RG6171 (Roche), AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), rettostrant (G1Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Lilly), and SHR9549 (Jiansu Hengrui Medicine); and SERMs, such as tamoxifen, raloxifene, toremifene, lasoxifene, bardoxifene, and aflixifen. GnRH analogues include degarelix, goserelin, histrelin, leuprolide, and triptorelin. Examples of peptide hormones include lanreotide, octreotide, and pasireotide. Examples of antiandrogens include abiraterone, apalutamide, bicalutamide, cyproterone acetate, enzalutamide, flutamide, and nilumid, and their pharmaceutically acceptable salts and solvates.

[0356] Monoclonal antibodies include: alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, gemtuzumab, inotuzumab ozogamicin, ipilimumab, mogamulizumab, and moxetumomab. pasudotox, necitumumab, nivolumab, ofatumumab, olaratumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tositumomab, and trastuzumab.

[0357] Taxanes include cabazitaxel, docetaxel, paclitaxel, and paclitaxel albumin-stabilized nanoparticle formulations (Nab-paclitaxel).

[0358] Topoisomerase inhibitors include etoposide, irinotecan, teniposide, and topotecan.

[0359] Vinca alkaloids include vinblastine, vincristine, and vinorelbine, and their pharmaceutically acceptable salts.

[0360] Other antitumor agents include: asparaginase (pegaspargase), bexarotene, eribulin, everolimus, hydroxyurea, ixabepilone, lenalidomide, mitotane, omacetaxine, pomalidomide, tagraxofusp, telotristat, temsirolimus, thalidomide, and venetoclax.

[0361] In some implementations, the additional anticancer agent is selected from the group consisting of: abiraterone acetate, acalabrutinib, trastuzumab / metasone, afatinib dimaleate, aflixifen, interleukin, alectinib, alenzab, apeliximab, amifostine, anastrozole, apalutamide, aprepitant, arsenic trioxide, asparaginase erwinia chrysanthemi, atezolizumab, avapritinib, avapritinib, and axicabtagene. ciloleucel), axitinib, azacitidine, AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), badoxifene, belistat, bendamustine hydrochloride, bevacizumab, besalodin, bicalutamide, bimetinib, bleomycin sulfate, bortezomib, bortezomib, besutinib, brentuximab velituximab, brigatinib, cabazitaxel, cabozantinib s-malate, calaspargase pegol-MKNL, capecitabine, caplacizumab-yhdp ), capmatinib hydrochloride, carboplatin, carfilzomib, carmustine, cimipril-rwlc, ceritinib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cobimetinib, kopanlix hydrochloride, crizotinib, cyclophosphamide, cytarabine, D-0502 (Inventisbio), dabrafenib mesylate, dacarbazine, dacomitinib, daratumumab, daratumumab and hyaluronidase-fihj, alpha-dabepoetin Alfa, Darolutamide, Dasatinib, Dornomycin Hydrochloride, Decitabine, Defibrotide Sodium, Degarelix, Denisulin, Denosumab, Dexamethasone, Dexrazoxane Hydrochloride, Detoximab, Docetaxel, Doxorubicin Hydrochloride, Duvalumab, Duvelix, Ellastran, Elotuzumab, Eltrombopag olamine, Emapalumab-LZSG, Etanerceptin Mesylate, Cannefenib, Enfortumab / Vidotrinevedotin-ejfv, entrectinib, enzalutamide, epirubicin hydrochloride, alpha-epotetin (epoetinalfa), erdafitinib, errebulin mesylate, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exemestane, fam-trastuzumab (drutecan-NXK), fedratinib hydrochloride, filgrastim, fludarabine phosphate, fluorouracil, flutamide, fostamatinib disodium, fulvestrant, gefitinib, gemcitabine hydrochloride, ozoguzumab ozogamicin), giglitinib fumarate, glaggib maleate, glucarpidase, goserelin acetate, granisetron, granisetron hydrochloride, hydroxyurea, ibritumomab Tiuxetan), ibrutinib, idarubicin hydrochloride, edalaris, ifosfamide, imatinib mesylate, imiquimod, oxintuzumab, recombinant interferon alpha-2b, iobenguane I-131, epasserti, ipilimumab, irinotecan hydrochloride, isatuximab-IRFC, ivosidenib, ixaprilone, ixazomib citrate, lanolepeptide acetate, lapatinib xylenesulfonate, larotrectinib sulfate, lasoxifen, lenalidomide, lenvatinib mesylate, letrozole, calcium leucovorin, leuprolide acetate, lomustine Lorlatinib, LSZ102 (Novartis), lurbinectedin, LY3484356 (Lilly), megestrol acetate, melphalan, melphalan hydrochloride, mercaptopurine, methotrexate, midotaurin, mitomycin C, mitoxantrone hydrochloride, mojazumab-kpkc, mosemumab-tdfk, nesetuzumab, nelarabine, neratinib maleate, nilotinib, nilumet, niraparib tosylate monohydrate, nivolumab, obinutuzumab, olfamumab, olaparib, omacetaxel Mepesuccinate), ondansetron hydrochloride, osimertinib mesylate, oxaliplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, palifermin, palonosetron hydrochloride, and pamidronate disodium.Disodium, Panitumumab, Pabipanaxetine, Pazopanib Hydrochloride, Pegaspargase, Pegfilgrastim, Peg-Glycol Interferon Alpha-2b, Perizumab, Pemetrexed Disodium, Pemigatinib, Pertuzumab, Pexidartinib Hydrochloride, Plerixafor, Polotuzumab Vedotin-PiiQ, Pomalidomide, Panatuzinib Hydrochloride, Pralatrexate, Prednisone, Procarbazine Hydrochloride, Propranolol Hydrochloride hydrochloride), radium-223 dichloride, raloxifene hydrochloride, ramucirumab, rasburicase, ravulizumab-cwvz, recombinant interferon α-2b, regorafenib, RG6171 (Roche), rettostrant, ripretinib, rituximab, rolapitant hydrochloride, romidisin, romiplostim, rucapapanediol camphor sulfonate, ruxotinib phosphate, sacituzumab govitecan-hziy, SAR439859 (Sanofi), selinexor, serpercatinib, selumetinib sulfate, SHR9549 (Jiansu Hengrui) Medicine), siltuximab, sipuleucel-t, sonodazole, sorafenib tosylate, tagrafranco-erzs, talimogenes razopanib tosylate, talimogenes razopanib.Laherparepvec, Tamoxifen Citrate, Tazemetostat Hydrobromide, Temozolomide, Tesirolimus, Thalidomide, Thioguanine, Thiotepa, Tisagenlecleucel, Tocilizumab, Topotecan Hydrochloride, Toremifene, Trabectin, Trametinib, Trastuzumab, Trastuzumab and Hyaluronidase-Oysk, Trifluuridine Hydrochloride and Tipyrimidine, Tucatinib, Triacetinib, Penrubicin, Vandetanib, Vemurafenib, Venetocin, Vincristine Sulfate, Vincristine Sulfate, Vinorelbine Tartrate, Vemmodega, Vorinostat, Zanubrutinib, Aflibercept, ZN-C5 (Zentalis), and Zoledronic Acid (acid), or the above-mentioned free base, pharmaceutically acceptable salt (including alternative salt forms of the salts named above), or solvate form, or combinations thereof.

[0362] The term “cancer” or “cancerous” refers to or describes a malignant and / or invasive growth or tumor caused by abnormal cell growth. As used herein, “cancer” refers to a solid tumor named for the type of cells that form it, as well as cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include (but are not limited to) sarcomas and carcinomas. Examples of blood cancers include (but are not limited to) leukemia, lymphoma, and myeloma. The term “cancer” includes (but is not limited to) primary cancer originating in a specific site in the body, metastatic cancer that has spread from its origin to other parts of the body, recurrence of the initial primary cancer after remission, and a second primary cancer that is a new primary cancer in people with a history of previous cancers of a different type than the latter.

[0363] The efficacy of the methods and uses described herein in certain tumors can be enhanced by combination with other approved or experimental cancer therapies, such as radiation, surgery, chemotherapy agents, targeted therapies, agents that inhibit other dysregulated signaling pathways in tumors, and other immune enhancers (such as PD-1 or PD-L1 antagonists). The methods and uses of this invention may further comprise one or more additional anticancer agents.

[0364] The application of the crystalline or amorphous form of the present invention may be affected by any method that enables the compound to be delivered to the site of action. Such methods include oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intramuscular, intravascular, or infusion), local administration, and rectal administration.

[0365] Dosing regimens can be adjusted to provide the optimal desired response. For example, the crystalline or amorphous forms of the present invention can be administered as a single bolus, in several separate doses administered over time, or the dose can be proportionally reduced or increased, as indicated by the urgency of the treatment situation. For ease of administration and uniformity of dosage, formulation of the therapeutic agent in unit dosage forms is particularly advantageous. As used herein, a unit dosage form refers to a physically discrete unit suitable for use as a unit dose in a mammalian subject to be treated; each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect, and the desired drug carrier. The specifications of the unit dosage forms of the present invention can be determined by and directly depend on: (a) the unique characteristics of the solid form and the specific therapeutic or preventative effect to be achieved, and (b) the inherent limitations in the techniques for mixing this active compound to treat an individual's sensitivity.

[0366] Therefore, those skilled in the art, based on the disclosure provided herein, will understand that dosages and administration regimens can be adjusted according to methods well known in therapeutic techniques. That is, the maximum tolerated dose can be easily established, and the effective amount providing measurable therapeutic benefit to the subject can also be determined, as well as the temporary requirement to administer each agent to provide measurable therapeutic benefit to the subject. Therefore, although certain dosages and administration regimens are illustrated herein, such examples in no way limit the dosages and administration regimens that can be provided to subjects in the practice of this invention.

[0367] It should be noted that dosage values ​​may vary depending on the type and severity of the symptom to be alleviated and may include single or multiple doses. It should be further understood that, for any particular subject, a specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the compound or pharmaceutical composition, taking into account factors such as the severity of the symptom or condition, the rate of administration, the distribution of the compound, and the prescribing physician's judgment. The dosage ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed solid forms or pharmaceutical compositions. For example, dosages may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Therefore, the present invention includes in-patient dose escalation determined by a person skilled in the art. Determining appropriate dosages and regimens for administering chemotherapeutic agents is well known in the relevant art and will be understood by a person skilled in the art to be included once the teachings disclosed herein are provided.

[0368] The dosage of the crystalline or amorphous form of the present invention is typically in single or fractional doses ranging from about 0.001 to about 100 mg / kg body weight / day, preferably from about 1 to about 35 mg / kg / day. For a 70 kg person, this totals from about 0.01 to about 7 g / day, preferably from about 0.02 to about 2.5 g / day. In some instances, dose levels below the lower limit of the above range may be sufficient, while in other cases, even larger doses may be used without causing any harmful side effects, provided that such larger doses are first divided into several smaller doses for administration throughout the day. The dose may be administered as a single dose (QD), or, as appropriate, may be subdivided into smaller doses suitable for BID (twice daily), TID (three times daily), or QID (four times daily) administration. Dosing regimens may be adjusted to provide optimal therapeutic response. For example, the dose may be reduced or increased proportionally, as specified by the urgency of the treatment situation, including temporarily or permanently reducing the dose if improvement or prevention of side effects is required.

[0369] The administration or dosing regimen may be repeated, or adjusted, as needed to achieve the desired treatment. As used herein, a “continuous dosing schedule” is an administration or dosing regimen without dose interruption, such as without treatment rest days. Repeating 21-day or 28-day treatment cycles without dose interruption between treatment cycles is an example of a continuous dosing schedule.

[0370] In some embodiments, the crystalline or amorphous form of the invention is administered at a daily dose of about 1 mg to about 1000 mg / day. In some embodiments, the crystalline or amorphous form of the invention is administered at a daily dose of about 10 mg to about 500 mg / day, and in some embodiments, it is administered at a dose of about 25 mg to about 300 mg / day. In some embodiments, it is administered according to a QD, BID, TID, or QID schedule at doses of about 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, Administer at doses of 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 260, 270, 275, 280, 290, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg.

[0371] The administration or dosing regimen may be repeated, or adjusted, as needed to achieve the desired treatment. An "intermittent dosing schedule" refers to an administration or dosing regimen that includes periods of dose interruption, such as treatment rest days. Repeating a 14 or 21-day treatment cycle with a 7-day treatment interruption between treatment cycles is an example of an intermittent dosing schedule. Such schedules with 2 or 3 weeks of treatment and 1 week of no treatment are sometimes referred to as 2 / 1-week or 3 / 1-week treatment cycles, respectively. Alternatively, intermittent dosing may consist of a 7-day treatment cycle with 5 days of treatment and 2 days of no treatment.

[0372] As used herein, a “continuous dosing schedule” is an administration or dosing regimen without dose interruption, such as without treatment rest days. Repeating a 21- or 28-day treatment cycle without dose interruption between treatment cycles is an example of a continuous dosing schedule.

[0373] In some embodiments, the crystalline or amorphous form of the present invention is administered via an intermittent dosing schedule. In other embodiments, the crystalline or amorphous form of the present invention is administered via a continuous dosing schedule.

[0374] "Pharmaceutical composition" means a mixture of one or more of the therapeutic agents described herein as active ingredients, or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients.

[0375] As used in this article, "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the active compound or therapeutic agent.

[0376] Pharmaceutically acceptable carriers may include any conventional pharmaceutical carriers or excipients. The choice of carrier and / or excipient will depend to a great extent on factors such as the specific administration method, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0377] In one embodiment, the present invention relates to a pharmaceutical composition comprising crystalline PF-07220060 monohydrate (form 2) and a pharmaceutically acceptable carrier or excipient.

[0378] In one embodiment, the present invention relates to a pharmaceutical composition comprising amorphous PF-07220060 and a pharmaceutically acceptable carrier or excipient.

[0379] Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents (such as hydrates and solvates). If desired, the pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, excipients, etc. Therefore, for oral administration, tablets containing various excipients (such as citric acid) along with various disintegrants (such as starch, alginate, and certain complex silicates) and binders (such as sucrose, gelatin, and gum arabic) can be used. Examples of excipients (without limitation) include calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Additionally, lubricants (such as magnesium stearate, sodium lauryl sulfate, and talc) are commonly used for tableting purposes. Similar types of solid pharmaceutical compositions can also be used in soft and hard-filled gelatin capsules. Therefore, non-limiting examples of materials include lactose (milk sugar) and high molecular weight polyethylene glycol. When an aqueous suspension or elixir is intended for oral administration, the active compound therein may be combined with various sweeteners or flavorings, colorings or dyes, and, if necessary, emulsifiers or suspending agents, along with diluents (such as water, ethanol, propylene glycol, glycerin, or combinations thereof).

[0380] The pharmaceutical compositions of the present invention may, for example, be in the form suitable for oral administration as tablets, capsules, pills, powders, sustained-release formulations, solutions, or suspensions; in the form suitable for parenteral injection as sterile solutions, suspensions, or emulsions; in the form suitable for topical application as ointments or creams; or in the form suitable for rectal administration as suppositories. The pharmaceutical compositions may be in the form of single-dose unit dosage forms suitable for precise dosing. The pharmaceutical compositions will comprise conventional pharmaceutical carriers or excipients and the compound according to the present invention as the active ingredient. Furthermore, they may comprise other medical or pharmaceutical agents, carriers, excipients, etc.

[0381] Exemplary parenteral formulations include solutions or suspensions of the active compound in sterile aqueous solutions, such as aqueous propylene glycol or dextran solutions. Such formulations may be appropriately buffered if desired.

[0382] Methods for preparing various pharmaceutical compositions having specific amounts of the active compound are known or will be apparent to those skilled in the art. See, for example, Remington, Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 19th edition (1995).

[0383] The crystalline and amorphous forms of the present invention can be administered orally. Oral administration may involve swallowing, allowing the therapeutic agent to enter the gastrointestinal tract, or it may be administered sublingually or by dispensing, allowing the therapeutic agent to enter the bloodstream directly from the mouth.

[0384] Dosage forms suitable for oral administration include solid dosage forms such as tablets, capsules containing particles, liquids or powders, lozenges (including liquid-filled ones), chewing gum, multiparticles and nanoparticles, gels, solid solutions, liposomes, membranes (including mucosal adhesives), ovules, sprays and liquid dosage forms.

[0385] Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as fillers in soft or hard capsules and typically contain a carrier, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, along with one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by, for example, rehydration of solids from a capsule.

[0386] The crystalline and amorphous forms of the present invention can also be used in rapidly dissolving and rapidly disintegrating formulations, such as those described in Liang and Chen (2001) Expert Opinion in Therapeutic Patents, 11(6), 981-986, the full text of which is incorporated herein by reference.

[0387] For tablet formulations, the crystalline or amorphous form of PF-07220060 may comprise 1% to 80% by weight of the formulation, more typically 5% to 60% by weight. In addition to the active agent, tablets typically contain a disintegrant. Examples of disintegrants include sodium glycolate starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant may comprise 1% to 25% by weight of the formulation, preferably 5% to 20% by weight.

[0388] Binders are commonly used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[0389] Tablets may also contain surfactants, such as sodium lauryl sulfate and polysorbate 80, and gliding agents, such as silica and talc, depending on the presence. When present, the surfactant is typically present in an amount of 0.2% to 5% by weight of the tablet, and the gliding agent is typically present in an amount of 0.2% to 1% by weight of the tablet.

[0390] Tablets typically also contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant is typically present in an amount of 0.25% to 10% by weight, preferably 0.5% to 3% by weight, of the tablet.

[0391] Other common ingredients include antioxidants, colorants, flavorings, preservatives, and taste masking agents.

[0392] An exemplary tablet may contain about 1% to about 80% by weight of an active agent, about 10% to about 90% by weight of a binder, about 0% to about 85% by weight of a diluent, about 2% to about 10% by weight of a disintegrant, and about 0.25% to about 10% by weight of a lubricant.

[0393] Tablet blends can be formed into tablets directly or by roller compression. The tablet blend or portions thereof may optionally be prepared prior to tableting by wet, dry, or melt granulation, melt coagulation, or extrusion. The final formulation may contain one or more layers and may be coated or uncoated; or encapsulated.

[0394] The formulation of tablets is discussed in detail in “Pharmaceutical Dosage Forms: Tablets, Volume 1” by H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 0-8247-6918-X), the full text of which is incorporated herein by reference.

[0395] Capsules (e.g., prepared from gelatin or HPMC), blisters for inhalers or blowpipes, and cartridges can be formulated as powder mixtures containing a therapeutic agent, a suitable powder matrix (such as lactose or starch), and a performance modifier (such as L-leucine, mannitol, or magnesium stearate). Lactose can be in anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0396] Solid dosage forms intended for oral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsatile, controlled, targeted, and programmed release.

[0397] Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies (such as high-energy dispersion and penetration, and coated particles) can be found in Verma et al., Current Status of Drug Delivery Technologies and Future Directions, Pharmaceutical Technology On-line, (2001) 25:1-14. The use of chewing gum to achieve controlled release is described in WO 00 / 35298. The full text of the disclosures of such references is incorporated herein by reference.

[0398] The crystalline and amorphous forms of the present invention can also be applied directly into the bloodstream, into muscles, or into internal organs. Suitable methods of parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0399] Parenteral preparations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably pH 3 to 9). However, for some applications, they may be more appropriately formulated as sterile non-aqueous solutions or as dry forms for use in conjunction with suitable media (such as sterile pyrogen-free water).

[0400] The preparation of parenteral preparations under aseptic conditions (e.g., by lyophilization) can be readily achieved using standard pharmaceutical techniques well known to those skilled in the art.

[0401] The solubility of therapeutic agents used to prepare parenteral solutions can potentially be increased by using appropriate formulation techniques, such as incorporation of solubilizers.

[0402] The crystalline and amorphous forms of the present invention can be presented in the form of a kit suitable for administering a pharmaceutical composition. Such a kit may contain an active agent in the form of a pharmaceutical composition comprising the active agent or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The kit may contain means for separately retaining the pharmaceutical composition, such as containers, separate vials, or separate foil packs. An example of such a kit is the common blister pack used for packaging tablets, capsules, etc. To aid compliance, the kit typically includes administration instructions and may include memory aids. The kit may further contain other materials suitable for administering the drug, such as diluents, fillers, IV bags and tubing, needles and syringes, etc.

[0403] In some preferred embodiments, the embodiment is selected from the group consisting of embodiments E1 to E52:

[0404] E1. A crystalline form (form 2) of 1,5-dehydrated-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060) monohydrate having resonance (ppm) values ​​of -126.1 and -125.6 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0405] E2. A crystalline form (form 2) of PF-07220060 monohydrate, having a powder X-ray diffraction (PXRD) pattern of peaks at 2θ values ​​of 9.6, 11.8 and 14.7°2θ ± 0.2°2θ.

[0406] E3. The crystalline form of implementation scheme E2, having a PXRD pattern of a peak at a 2θ value of 12.4°2θ ± 0.2°2θ.

[0407] E4. The crystalline form of implementation E2 or E3, having a PXRD pattern of a peak at a 2θ value of 21.0°2θ ± 0.2°2θ.

[0408] E5. Implementation scheme E2, E3 or E4 crystalline form, having a crystal structure containing 1484, 1555 and 1587 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0409] E6. The crystalline form of implementation scheme E5, which further comprises 1387 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0410] E7. The crystalline form of implementation scheme E5 or E6, which further comprises 1395 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0411] E8. A crystalline form according to any one of embodiments E2 to E7, having resonance (ppm) values ​​of 22.8 and 163.0 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0412] E9. The crystalline form of embodiment E8, having one, two, or three resonance (ppm) values ​​additionally comprising a group consisting of 50.3, 109.8, and 129.1 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0413] E10. A crystalline form of any one of embodiments E2 to E9, having a resonance (ppm) value of -126.1 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0414] E11. A crystalline form of any one of embodiments E2 to E10, having an additional resonance (ppm) value comprising -125.6 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0415] E12. A crystalline form (form 2) of PF-07220060 monohydrate, having resonance (ppm) values ​​of 22.8 and 163.0 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0416] E13. The crystalline form of embodiment E12, having one, two, or three resonance (ppm) values ​​additionally comprising a group consisting of 50.3, 109.8, and 129.1 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0417] E14. A crystalline form (form 2) of PF-07220060 monohydrate, having crystalline structures containing 1484, 1555, and 1587 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0418] E15. Crystalline form of implementation scheme E14, which further comprises 1387 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0419] E16. Implementation scheme E13 or E14 crystalline form, which further comprises 1395 cm -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0420] E17. A crystalline form (form 2) of PF-07220060, having: (a) powder X-ray diffraction (PXRD) patterns containing peaks at 2θ values ​​of 9.6, 11.8, and 14.7°2θ ± 0.2°2θ; (b) peaks containing peaks at 1484, 1555, and 1587 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 (c) Raman spectra of values ​​of 22.8 and 163.0 ppm ± 0.2 ppm; 13 C solid-state NMR spectrum; or (d) resonance (ppm) values ​​including -126.1 and -125.6 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum; or any combination of (a), (b), (c) and (d).

[0421] E18. An anhydrous crystalline form (form 6) of PF-07220060, having resonance (ppm) values ​​of -132.4 and -131.1 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0422] E19. An anhydrous crystalline form (form 6) of PF-07220060, having a resonance (ppm) value of -132.4 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0423] E20. An anhydrous crystalline form (form 6) of PF-07220060, having a resonance (ppm) value of -131.1 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0424] E21. An anhydrous crystalline form (form 6) of PF-07220060, having a powder X-ray diffraction (PXRD) pattern containing peaks at the following 2θ values:

[0425] (a) 6.8 and 10.1°2θ±0.2°2θ;

[0426] (b) 6.8, 10.1 and 12.2°2θ ± 0.2°2θ;

[0427] (c) 6.8, 10.1 and 17.8°2θ±0.2°2θ;

[0428] (d) 6.8, 10.1, 12.2 and 17.8°2θ±0.2°2θ;

[0429] (e) 8.5, 10.1, and 13.8°2θ ± 0.2°2θ;

[0430] (f) 6.8, 8.5 and 13.8°2θ ± 0.2°2θ;

[0431] (g) 6.8, 8.5, 10.1 and 13.8°2θ±0.2°2θ; or

[0432] (h)6.8, 8.5, 10.1, 12.2 and 13.8°2θ±0.2°2θ.

[0433] E22. A crystalline form according to any one of embodiments E18 to E21, having a crystalline structure containing 1436, 1465, and 1566 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0434] E23. A crystalline form according to any one of embodiments E18 to E22, having a resonance (ppm) value comprising 54.7, 112.6, and 132.8 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0435] E24. The crystalline form of embodiment E23, having a resonance (ppm) value of 49.2 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0436] E25. A crystalline form according to any one of embodiments E18 to E22, having two, three, or four resonance (ppm) values ​​comprising a group selected from 49.2, 54.7, 112.6, and 132.8 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0437] E26. A crystalline form according to any one of embodiments E18 to E25, having a resonance (ppm) value of -132.4 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0438] E27. A crystalline form according to any one of embodiments E18 to E26, having an additional resonance (ppm) value comprising -131.1 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

[0439] E28. An anhydrous crystalline form (form 6) of PF-07220060, having resonance (ppm) values ​​of 54.7, 112.6, and 132.8 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0440] E29. The crystalline form of embodiment E28, having an additional resonance (ppm) value of 49.2 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

[0441] E30. An anhydrous crystalline form (form 6) of PF-07220060, having 1436 and 1566 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0442] E31. The crystalline form of implementation scheme E30, which further comprises 1465 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values.

[0443] E32. An anhydrous crystalline form (form 6) of PF-07220060, having:

[0444] (a) Powder X-ray diffraction (PXRD) pattern of peaks at the following 2θ values:

[0445] (i) 6.8 and 10.1°2θ±0.2°2θ;

[0446] (ii) 6.8, 10.1 and 12.2°2θ±0.2°2θ;

[0447] (iii) 6.8, 10.1 and 17.8°2θ±0.2°2θ;

[0448] (iv) 6.8, 10.1, 12.2 and 17.8°2θ±0.2°2θ;

[0449] (v) 8.5, 10.1 and 13.8°2θ±0.2°2θ;

[0450] (vi) 6.8, 8.5 and 13.8°2θ±0.2°2θ;

[0451] (vii) 6.8, 8.5, 10.1 and 13.8°2θ±0.2°2θ; or

[0452] (viii) 6.8, 8.5, 10.1, 12.2 and 13.8°2θ±0.2°2θ.

[0453] (b) Includes 1436, 1465 and 1566 cm -1 ±2cm -1 wavenumber (cm) -1 Raman spectra of values;

[0454] (c) Includes resonance (ppm) values ​​of 54.7, 112.6, and 132.8 ppm ± 0.2 ppm. 13 C solid-state NMR spectrum; or

[0455] (d) Resonance (ppm) values ​​including -132.4 and -131.1 ppm ± 0.2 ppm 19 F solid-state NMR spectrum;

[0456] Or any combination of two or more of (a), (b), (c) and (d).

[0457] E33. An anhydrous crystalline form (form 11) of PF-07220060, which has the same properties as... Figure 17 The powder X-ray diffraction (PXRD) patterns are essentially the same.

[0458] E34. The crystalline form of any one of the implementation schemes E1 to E17, wherein the crystalline form is substantially pure crystalline PF-07220060 monohydrate (form 2).

[0459] E35. The crystalline form of any one of implementation schemes E18 to E32, wherein the crystalline form is substantially pure anhydrous crystal PF-07220060 (form 6).

[0460] E36. The crystalline form of implementation scheme E33, wherein the crystalline form is substantially pure anhydrous crystal PF-07220060 (form 11).

[0461] E37. A pharmaceutical composition comprising a crystalline form of any one of embodiments E1 to E17 and E34, and a pharmaceutically acceptable carrier or excipient.

[0462] E38. A pharmaceutical composition comprising a crystalline form of any one of embodiments E18 to E32 and E35, and a pharmaceutically acceptable carrier or excipient.

[0463] E39. An amorphous form (form 8) of PF-07220060.

[0464] E40. The amorphous form of embodiment E39 has a powder X-ray diffraction (PXRD) pattern containing broad peaks at diffraction angles (2θ) from about 4 to about 40°2θ ± 0.5°2θ.

[0465] E41. The amorphous form of implementation scheme E39 or E40, which has the same Figure 8 The powder X-ray diffraction (PXRD) pattern is essentially the same.

[0466] E42. An amorphous form according to any one of embodiments E39 to E41, having a resonance (ppm) value containing -127.5ppm ± 0.5ppm. 19 F solid-state NMR spectrum.

[0467] E43. The amorphous form of embodiment E42, having resonance (ppm) values ​​of 20.9, 49.3, and 116.6 ppm ± 0.5 ppm. 13 C solid-state NMR spectroscopy.

[0468] E44. An amorphous form of any one of embodiments E39 to E43, wherein the amorphous form is substantially pure amorphous PF-07220060 (form 8).

[0469] E45. A pharmaceutical composition comprising an amorphous form according to any one of embodiments E39 to E44, and a pharmaceutically acceptable carrier or excipient.

[0470] E46. A method of treating a subject with cancer, comprising administering to the subject a therapeutically effective amount of the crystalline form of any one of embodiments E1 to E36 or the amorphous form of any one of embodiments E39 to E45.

[0471] E47. A method of treating a subject with cancer, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of embodiment E37, E38, or E45.

[0472] E48. Implement the method of E46 or E47, wherein the cancer is selected from the group consisting of: breast cancer, prostate cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, uterine cancer, pancreatic cancer, stomach cancer, colorectal cancer, esophageal cancer, head and neck cancer, testicular cancer, adrenal cancer, skin cancer, brain cancer, sarcoma, and lymphoma.

[0473] E49. The crystalline form of any one of embodiments E1 to E36 or the amorphous form of any one of embodiments E39 to E45, for the treatment of cancer.

[0474] E50. A pharmaceutical composition according to implementation plan E37, E38 or E45, used for the treatment of cancer.

[0475] E51. The crystalline form of embodiment E49 or the pharmaceutical composition of E50, wherein the cancer is selected from the group consisting of: breast cancer, prostate cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, uterine cancer, pancreatic cancer, gastric cancer, colorectal cancer, esophageal cancer, head and neck cancer, testicular cancer, adrenal cancer, skin cancer, brain cancer, sarcoma, and lymphoma.

[0476] E52. Use of a crystalline form of any one of embodiments E1 to E36 or an amorphous form of any one of embodiments E39 to E45 for the preparation of a medicament for treating cancer. Example

[0477] The following examples and preparation methods further illustrate and demonstrate aspects and embodiments of the invention. It should be understood that the scope of the invention is not limited by the scope of the following examples.

[0478] General Method 1A. Powder X-ray Diffraction (PXRD)

[0479] Instrumentation and Methods:

[0480] Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a copper radiation source. The diverging slit was set under continuous illumination at 15 mm. The diffracted radiation was detected using a PSD-Lynx Eye detector with the PSD aperture set at 2.99°. The X-ray tube voltage and ampere were set to 40 kV and 40 mA, respectively. The diffraction was performed at copper (Cu) wavelengths. Data were collected from 3.0 to 40.0°2-θ using an θ-θ goniometer. For forms 2, 6, and 8, a step size of 0.01° and a step time of 1.0 second were used. For form 11, a step size of 0.02° and a step time of 0.3 seconds were used. The antiscattering screen was set to a fixed distance of 1.5 mm. The sample was rotated during data collection. The sample was prepared by placing it in a silicon low-background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software and analyzed using EVA diffraction plus software.

[0481] Peak picking method:

[0482] The PXRD data file is not processed before peak search. A peak search algorithm is used in the EVA software, and peaks with a threshold of 1 are selected for initial peak assignment. To ensure effectiveness, manual adjustments are made; the automatically assigned output is visually checked, and peak positions are adjusted to their maximum values. Peaks with a relative intensity of ≥3% are generally selected. Peaks that are not resolved or consistent with noise are typically not selected. The typical error associated with the peak positions of the PXRD specified in the USP is at most ±0.2°²-θ for crystalline forms (USP-941) and at most ±0.5°²-θ for amorphous forms.

[0483] General Method 1B. Powder X-ray Diffraction (PXRD)

[0484] Instrumentation and Methods:

[0485] Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a copper radiation source. The diverging slit was set under continuous illumination at 10 mm. Diffracted radiation was detected using a LYNXEYE_EX detector, with the second slit set at 5.50 mm. The X-ray tube voltage and ampere were set to 40 kV and 40 mA, respectively. For form 1, a step size of 0.02° and a step time of 0.5 seconds were used at Cu wavelengths (…). Data were collected from 3.0 to 40.0°2-θ using an θ-θ goniometer. An anti-scattering screen was positioned appropriately. Samples were prepared by placing them in a silicon low-background sample holder and rotating them during collection. Data were collected using Bruker DIFFRAC Plus software and analyzed using EVA diffraction plus software.

[0486] Peak selection:

[0487] The PXRD data file is not processed before peak search. A peak search algorithm is used in EVA software, and peaks with a threshold of 1 are selected for initial peak assignment. To ensure effectiveness, manual adjustments are made; the automatically assigned output is visually checked, and peak positions are adjusted to their maximum values. Peaks with a relative intensity of ≥3% are generally selected. Typically, unresolved peaks or those consistent with noise are not selected. The typical error associated with the peak positions of the PXRD specified in the USP is at most ±0.2°²-θ for crystalline forms (USP-941) and at most ±0.5°²-θ for amorphous forms.

[0488] General Method 2. Raman Spectroscopy

[0489] Instrumentation and Methods:

[0490] Raman spectra were collected using a Thermo Scientific iS50 FT-Raman attachment attached to the FT-IR stage. A CaF2R beam splitter was used in the FT-Raman configuration. The spectrometer was equipped with a 1064 nm diode laser and a room-temperature InGaAs detector. Instrument performance and calibration were performed using polypropylene prior to data acquisition. Samples were analyzed as tablets in glass NMR tubes or in suitable sample holders kept stationary during data acquisition. Spectra were collected using laser power between 0.1 and 0.5 W and 512 co-added scans. The collection range was 3700 to 100 cm⁻¹. -1 Use 2cm -1 Analyze the recorded API spectra and apply the Happ-Genzel apodization method to all spectra. Record multiple spectra; the reported spectra represent two points.

[0491] Peak picking method:

[0492] Intensity scales were normalized to 1 before peak picking. Peaks were manually identified using Thermo Nicolet Omnic 9.7.46 software. Peak positions were picked at the peak maximum, and peaks were identified as is if slopes existed on each side; shoulders were not included. For pure PF-07220060 form 2, an absolute threshold of 0.06 and a sensitivity of 75 were used during peak picking. Peak positions were rounded to the nearest integer using standard practice (rounding up 0.5, rounding down 0.4). Peaks with normalized peak intensities between (1-0.75), (0.74-0.30), and (0.29-0) were labeled as strong, moderate, and weak, respectively.

[0493] General Method 3. 13 C solid-state NMR (ssNMR) spectrum

[0494] Instrumentation and Methods:

[0495] Positioned at Bruker-BioSpin Avance III 500MHz ( 1 Solid-state NMR (ssNMR) analysis was performed on a CPMAS probe in an H-frequency NMR spectrometer. The material was packed into a 4 mm rotor. A magic angle rotation rate of 15.0 kHz was used. Spectra were collected at ambient temperature (uncontrolled temperature).

[0496] The cross-polarization magic angle rotation (CPMAS) experiment using proton decoupling collected data. 13 CssNMR spectroscopy. A phase-tuned proton decoupling field of 80–100 kHz was applied during spectral acquisition. The cross-polarization contact time was set to 2 ms. A recirculation delay of 3.25 seconds was used for Form 1, and 3.5 seconds was used for Forms 2, 6, and 8 to collect spectra. The scan number was adjusted to obtain a sufficient signal-to-noise ratio. 13 C chemical shift scale used 13 The C CPMAS experiment referenced an external standard for crystalline adamantane, with its high magnetic field resonance set at 29.5 ppm.

[0497] Magic-angle spin (MAS) experiment using proton decoupling to collect 19 F ss NMR spectroscopy. A phase-tuned proton decoupling field of 80–100 kHz was applied during spectral acquisition. A 5.25-second recirculation delay was used for Form 1 spectra. A 45-second recirculation delay was used for Form 2 spectra. Spectra were collected using a 29-second recirculation delay for Form 6 and a 5-second recirculation delay for Form 8. The scan number was adjusted to obtain a sufficient signal-to-noise ratio. 19 F chemical shift scale used 19The FMAS experiment was referenced against an external standard of trifluoroacetic acid and water (50% / 50% v / v), with its resonance set to -76.54 ppm.

[0498] Peak picking method:

[0499] Automated peak picking was performed using Bruker-BioSpin TopSpin version 3.6 software. Generally, a threshold of 5% relative intensity was used for initial peak selection. The output of the automated peak picking was visually inspected to ensure effectiveness, and manual adjustments were made if necessary. Although specific solid-state NMR peaks are reported in this paper, such ranges do exist due to variations in instrumentation, sample, and sample preparation. This is standard practice in solid-state NMR techniques because peak positions inherently vary. 13 C and 19 The typical variability of the F chemical shift x-axis value is plus or minus (±) 0.2 ppm for crystalline solids and plus or minus (±) 0.5 ppm for amorphous solids. The solid-state NMR peak heights reported in this paper are relative intensities. Solid-state NMR intensities can be adjusted based on actual experimental parameter settings and the thermal history of the sample.

[0500] General Method 4. Thermogravimetric Analysis (TGA)

[0501] Thermogravimetric analysis was performed using a Discovery TGA (TA instruments) thermogravimetric analyzer. Approximately 10 mg of sample was weighed into an aluminum pan and heated to 250 °C from the ambient temperature (approximately 20 °C) at a heating rate of 10 °C / min under nitrogen purging (10 mL / min for both the sample chamber and the balance).

[0502] General Method 5A. Differential Scanning Calorimetry (DSC)

[0503] Modulated differential scanning calorimetry (DSC) measurements were performed using a Discovery DSC (TA instruments) equipped with a refrigeration cooling accessory. All experiments were conducted in a standard / Tzero aluminum dish. Indium was used to determine the cell constant, and indium and tin were used as standards for temperature calibration. All measurements were performed under continuous dry nitrogen purging (50 mL / min). Approximately 1 to 5 mg of solid sample was weighed into the Tzero aluminum dish, loosely sealed, and heated from -40 °C to 220 °C at a heating rate of 10 °C / min. Experimental data were analyzed using commercially available software (TA Universal Analysis 2000 / Trios software, TA Instruments).

[0504] General Method 5B. Differential Scanning Calorimetry (DSC)

[0505] DSC measurements were performed using a Discovery DSC (TA instruments) equipped with a refrigeration cooling accessory. All experiments were conducted in a standard / Tzero aluminum pan. Indium was used to determine the cell constant, and indium and tin were used as standards for temperature calibration. All measurements were performed under continuous dry nitrogen purging (50 mL / min). Approximately 7 mg of solid sample was weighed into the Tzero aluminum pan, loosely sealed, and heated from -40 °C to 165 °C using a temperature adjustment range of ±1 °C, a modulation period of 100 seconds, and a ramp rate of 2 °C / min. Experimental data were analyzed using commercially available software (TA Universal Analysis 2000 / Trios software, TA Instruments).

[0506] General Method 6. Moisture Adsorption (Hygroscopicity)

[0507] Water adsorption and desorption studies were performed on an automated vapor adsorption analyzer (TA Instruments Q5000 SA). A microbalance was calibrated using 100 mg standard weights. The relative humidity (RH) sensor was calibrated using a saturated salt solution at 5.0, 11.3, 32.8, 52.8, 75.3, and 84.3% RH (25°C). Approximately 10 to 20 mg of powder sample was placed in a quartz sample holder and dried at 60°C at ≤3% RH. Equilibrium was assumed to have been reached when the sample weight change was <0.001 wt% within 5 minutes or at the maximum equilibrium time of 300 minutes. RH was then gradually increased to 90% in 10% increments, followed by decreasing to a final 10% RH in 10% increments. Again, equilibrium was assumed to have been reached when the sample weight change was <0.001 wt% within 5 minutes or at the maximum equilibrium time of 300 minutes. Weight increases at 60% RH were based on the weight after the initial drying step.

[0508] Example 1

[0509] Preparation of PF-07220060 monohydrate (form 2)

[0510]

[0511] Two reactions were run in parallel in compressible vials (labeled Vial A and Vial B). The reactions were run under the same conditions and scale, but the separation and recrystallization procedures for Vial A and Vial B were different, as shown below.

[0512] Each 20 mL pressable vial was equipped with a stir bar and 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(prop-2-yl)-1H-benzimidazol-2-yl]prop-2-ol (intermediate (In.) 1, prepared as described in Example A94 of U.S. Patent No. 10,233,188) (1.48 g, 3.865 mmol), 3-amino-1,5-dehydro-2,3-dideoxy-D-threo-pentitol hydrochloride (intermediate 2A) (0.68 g, 4.44 mmol), and acetonitrile (MeCN) (15 mL) was added. Diisopropylethylamine (DIPEA) (1.745 g, 2.35 mL, 13.5 mmol) was added, the vials were press-fitted, and the vials were heated to 85°C in a heating mantle and stirred for 17 hours.

[0513] After slight cooling, precipitation was observed. LCMS analysis of aliquots showed an 80:20 mixture of product and starting material. The internal temperature was measured at 76°C. The vials were heated to an internal temperature of 85°C, and the turbid mixture was then heated at this temperature for 21 hours. LCMS analysis of aliquots showed a 92:8 mixture of product and starting material.

[0514] Transfer the reaction mixture from each vial to a round-bottom flask and reduce the volume by one-third, then stir at room temperature for 1 hour. Filter the mixture to remove any precipitated inorganic solids.

[0515] The filtrate was seeded with approximately 1 mg of PF-07220060 hydrate (form 1) prepared as described in Example A94 of U.S. Patent No. 10,233,188. A turbid suspension formed after several minutes. The mixture was slowly stirred at room temperature for 2 days. The thick slurry was filtered, and the flask was rinsed with a small volume of acetonitrile to facilitate transfer, and the solids were rinsed with 10% MeCN / diisopropyl ether (DIPE).

[0516] Bottle A: PF-07220060 Hydrate (Form 1)

[0517] Reduce the MeCN / DIPE filtrate to the minimum volume. Partition the residue between ethyl acetate (EtOAc) and water and separate the layers. Extract the aqueous layer again with EtOAc. Wash the combined organic layers with brine, dry over MgSO4, and filter. Reduce the filtrate to the minimum volume to give 1.75 g of amber residue.

[0518] The residue was dissolved in 18 mL of MeCN and stirred at room temperature. After a few minutes, the solid began to precipitate from the solution without crystallization. The suspension was covered with lens paper and stirred overnight. The MeCN suspension was filtered and the solid was washed with 10% MeCN / DIPE and then dried overnight in a vacuum oven (without heating) to give 834 mg of white solid. This solid provided a PXRD pattern consistent with that of a genuine sample of PF-07220060 hydrate (form 1) prepared as described in Example A94 of U.S. Patent No. 10,233,188. Figure 5 ).

[0519] Vial B: PF-07220060 Monohydrate (Form 2)

[0520] The MeCN / DIPE filtrate was concentrated to dryness and the solid was dried in a vacuum oven at 55°C for about 1 hour to obtain 1.8 g of a slightly viscous, grayish-white solid. LCMS and 1 1H NMR analysis revealed that the solid was contaminated with DIPEA hydrochloride. The solid was resuspended in 18 mL of 10% MeCN / water to obtain a thick slurry, which was further diluted with another 18 mL of 10% MeCN / water. The thick mixture was stirred at room temperature for 20 minutes, then filtered and washed with 130 mL of 10% MeCN / water.

[0521] The solid was dried overnight in a vacuum oven at 55°C to obtain 1.75 g of crystalline material. After further characterization, the material was determined to have a new PXRD pattern (…). Figure 1 It was identified as PF-07220060 monohydrate (form 2). Elemental analysis was performed in the presence of 1.0 equivalent water. For C... 22 H 27 Analytical values ​​of N5O3FCl.1.0H2O: C: 54.82; H: 6.07; N: 14.53; Cl: 7.36; Measured values: C: 54.73, 54.81; H: 6.08, 6.12; N: 14.42, 14.45; Cl: 7.19.

[0522] Example 2

[0523] Alternative preparation of PF-07220060 monohydrate (form 2)

[0524] Step 1: 1,5-Dehydr-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060).

[0525]

[0526] Acetonitrile (45 L, 5 vol) was added to a 200 L reactor purged with nitrogen. The reactor was set to a jacket temperature (Tj) of 25 °C ± 5 °C, and 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(prop-2-yl)-1H-benzimidazol-2-yl]prop-2-ol (Int. 1, 9 kg, 23.34 mol) and 3-amino-1,5-dehydr-2,3-dideoxy-D-threo-pentitol (Int. 2B, 3.867 kg, 32.68 mol, 1.4 equivalents) were added. The mixture was stirred at a moderate speed for at least 10 minutes, after which DIPEA (8.132 L, 46.68 mol, 2 equivalents) was added. The reactor was set to a Tj of 80 °C ± 5 °C, and the reaction was heated under a nitrogen atmosphere for 36 hours. A second addition of DIPEA (2 L, 11.67 mol, 0.5 equivalents) was required to further heat the mixture at a temperature of 80 °C ± 5 °C for 6 hours, pushing the reaction to 97% completion. Then, treatment water (45.00 L, 5 volumes) was added over 20 minutes, while maintaining the temperature at 75 °C ± 10 °C. The reaction was then cooled to 25 °C ± 5 °C over 60 minutes and held at this temperature for 18 hours.

[0527] The solvent was reduced to approximately 35% by volume under a light vacuum and used to induce crystal formation in the resulting solution by cooling / scraping 30 mL aliquots outside the reactor. After crystallization, the resulting mixture was granulated at room temperature over 18 hours.

[0528] The crude product PF-07220060 was collected by filtration through a Nutsche filter and the filter cake was washed with MeCN / water (45 L, 10 volumes, 1:1 mixture) and dried under nitrogen to give crude 1,5-dehydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060) (10 kg, 94.38% yield, UPLC purity 97%).

[0529] Step 1R: 1,5-dehydr-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol monohydrate (PF-07220060) (Form 2).

[0530]

[0531] In a 200 L reactor, isopropanol (100 L, 10 volumes) and crude 1,5-dehydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060, 10 kg, 21.56 mol) were added. The reactor was set to Tj at 40 °C ± 15 °C and the mixture was stirred under nitrogen until complete dissolution was achieved (60 min). The solution was cooled to 25 °C ± 5 °C and transferred to a holding drum.

[0532] In a 200L reactor, treated water (135L, 13.5 volume) was added using a particulate filter. The reactor was set to a Tj of 40℃ ± 5℃, and an isopropanol solution containing the product was added to the reactor through a polypropylene particulate filter while simultaneously distilling under vacuum. The transfer rate and reactor pressure were adjusted as needed to distill the isopropanol, while maintaining a constant volume of approximately 135L and a water-to-isopropanol ratio of approximately 85 / 15 in the 200L vessel. Once the addition was complete, the product was granulated for 48 hours and the particle size was reduced using high-shear wet milling.

[0533] The product was filtered through a Nutsche filter and the filter cake was washed with 27 L of treatment water and dried under vacuum. The product was transferred to an oven tray and further dried under vacuum at 30 °C ± 10 °C for 4 hours to give 1,5-dehydrated-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060) monohydrate (form 2) (9.2 kg, 81% yield, UPLC purity 98.6%).

[0534] Example 3

[0535] Characterization of PF-07220060 monohydrate (form 2)

[0536] The PF-07220060 monohydrate (form 2) prepared according to Example 2 is characterized as follows:

[0537] PXRD data

[0538] Figure 1 The PXRD data for PF-07220060 monohydrate (form 2) collected according to general method 1A are shown. Table 1 provides a list of PXRD peaks and their relative intensities at diffraction angles of 2 - θ° (°2θ) ± 0.2°2θ.

[0539] Table 1: List of PXRD peaks (2-θ°) for PF-07220060 monohydrate (form 2)

[0540]

[0541] FT-Raman Data

[0542] Figure 2 The FT-Raman spectra of PF-07220060 monohydrate (form 2) collected according to general method 2 are shown in Table 2. (In cm⁻¹) -1 ±2cm -1 The FT-Raman peak (cm) is represented by -1 A complete list of peak intensities and qualitative intensities. The following represents the normalized peak intensities: w = weak; m = moderate; s = strong.

[0543] Table 2: List of FT Raman peaks (cm) for PF-07220060 monohydrate (form 2) -1 )

[0544]

[0545]

[0546] ssNMR data

[0547] Figure 3 The carbon CPMAS spectrum of PF-07220060 monohydrate (form 2) collected according to general method 3 is shown. Chemical shifts are expressed in parts per million (ppm) and referenced to an external sample of solid-phase adamantane at 29.5 ppm. SSNMR of form 2 is provided in ppm ± 0.2 ppm in Table 3. 13 List of C chemical shifts (ppm).

[0548] Table 3: ssNMR of PF-07220060 monohydrate (form 2) 13 C chemical shift (ppm)

[0549]

[0550] Figure 4 The image shows the PF-07220060 monohydrate (form 2) collected according to general method 3. 19 F ss NMR spectra. Chemical shifts are expressed in parts per million (ppm) and their resonance is set to -76.54 ppm (as determined by pure TMS) with reference to an external standard of trifluoroacetic acid and water (50 / 50 volume / volume).

[0551] Table 4. PF-07220060 monohydrate (form 2)19 F solid-state NMR peak list (ppm).

[0552]

[0553] Example 4

[0554] Comparative example: Preparation of PF-07220060 hydrate (form 1)

[0555]

[0556] PF-07220060 hydrate (Form 1) was prepared as a white crystalline solid according to the procedure described in Example A94 of U.S. Patent No. 10,233,188. The crystalline solid was determined to be a hydrate with an indeterminate stoichiometry and was identified as PF-07220060 hydrate (Form 1).

[0557] Example 5

[0558] Comparative Example: Alternative Preparation of PF-07220060 Hydrate (Form 1)

[0559] Example 5A: Crystalline PF-07220060 monohydrate (form 2) (348 mg) prepared as described in Example 2 was stirred with acetonitrile (3.00 mL) at room temperature. After stirring for approximately 24 hours, a small aliquot (approximately 0.1 mL) was taken from the mixture for PXRD analysis. The remaining material was stirred for another day. After a total of two days of stirring, the white solid was collected by vacuum filtration and washed with acetonitrile (2 × 0.500 mL). 282 mg, 81%. PXRD confirmed that the solid had been converted to PF-07220060 hydrate (form 1).

[0560] Example 5B: PF-07220060 monohydrate (form 2) (1.01529 g) prepared as described in Example 2 was combined with acetonitrile (10.0 mL). After stirring for 3 days, the solid was collected by vacuum filtration and dried on a glass frit filter. The crystalline solid was determined to be PF-07220060 hydrate (form 1).

[0561] Example 6

[0562] Characterization of PF-07220060 hydrate (form 1)

[0563] The PF-07220060 hydrate (form 1) prepared as described in Example 5B is characterized as follows:

[0564] PXRD data

[0565] Figure 5 This shows the PXRD data of PF-07220060 hydrate (form 1) collected according to general method 1B.

[0566] ssNMR data

[0567] Figure 6 The carbon CPMAS spectrum of PF-07220060 hydrate (form 1) collected according to general method 3 is shown. Chemical shifts are expressed in parts per million (ppm) and referenced to an external sample of solid-phase adamantane at 29.5 ppm. SSNMR of form 1 is provided in ppm ± 0.2 ppm in Table 5. 13 List of C chemical shifts (ppm).

[0568] Table 5: ssNMR of PF-07220060 hydrate (form 1) 13 C chemical shift (ppm)

[0569]

[0570] Figure 7 The image shows PF-07220060 hydrate (form 1) collected according to general method 3. 19 F ssNMR spectra. Chemical shifts are expressed in parts per million (ppm) and their resonance is set to -76.54 ppm (as determined by pure TMS) with reference to an external standard of trifluoroacetic acid and water (50 / 50 volume / volume). ssNMR spectra of Form 1 are provided in ppm ± 0.2 ppm in Table 6. 19 List of F chemical shifts (ppm).

[0571] Table 6. List of 19F solid-state NMR peaks (ppm) of PF-07220060 hydrate (form 1).

[0572]

[0573] Example 7

[0574] The transformation of PF-07220060 hydrate (form 1) to PF-07220060 monohydrate (form 2).

[0575] The crystalline PF-07220060 hydrate (form 1) (25 mg) prepared as described in vial A of Example 1 was suspended in 10% MeCN / water (0.5 mL) and slurried at room temperature for about 30 minutes. PXRD confirmed that aliquots of the suspension had been converted to PF-07220060 monohydrate (form 2).

[0576] Example 8

[0577] Preparation of amorphous PF-07220060 (Form 8)

[0578]

[0579] The PF-07220060 monohydrate (form 2) (331.7 mg) prepared as described in Example 2 was melted in a small aluminum dish at approximately 165°C. The resulting pale yellow liquid was placed in ice water and rapidly cooled. The liquid turned into a pale yellow transparent solid. The solid was transferred to a vial and crushed into a pale yellow powder with a spatula, which was determined by PXRD to be amorphous PF-07220060 (form 8) (294.2 mg, 89%).

[0580] Example 9

[0581] Alternative preparation of amorphous PF-07220060 (Form 8)

[0582]

[0583] The PF-07220060 monohydrate (form 2) (approximately 2 g) prepared as described in Example 2 and acetonitrile (100 mL) were combined and sonicated for 5 minutes. The sample was then placed in a 50°C water bath for 15 minutes until the solid was completely dissolved. Water (5.0 mL) was added, and the sample was sonicated again for 5 minutes. The resulting solution was filtered through a 0.20 mm PTFE filter. The filtrate was frozen in a dry ice / acetone bath and placed in a Labconco FreezeZone - 105°C freeze-dryer. The sample was kept in the freeze-dryer until all solvent was removed.

[0584] Example 10

[0585] Characterization of amorphous PF-07220060 (Form 8)

[0586] The amorphous PF-07220060 (form 8) prepared as described in Example 9 is characterized as follows:

[0587] PXRD data

[0588] Figure 8 Displays PXRD data for amorphous PF-07220060 (Form 8) collected according to general method 1A.

[0589] Variable modulation differential scanning calorimetry (DSC)

[0590] Figure 9 The modulated DSC scan of amorphous PF-07220060 (Form 8) collected according to general method 5B shows a glass transition temperature (Tg) of 102 °C ± 5 °C.

[0591] FT-Raman Data

[0592] Figure 10 The FT-Raman spectra of amorphous PF-07220060 (form 8) collected according to general method 2 are shown in Table 7. The spectra are expressed in cm⁻¹. -1 ±2cm -1 Provides FT-Raman Peak (cm) -1 A complete list of normalized peak intensities is provided. The following indicates the normalized peak intensities: w = weak; m = moderate; s = strong.

[0593] Table 7. List of FT Raman peaks (cm) for amorphous PF-07220060 (Form 8) -1 )

[0594]

[0595]

[0596] ssNMR data

[0597] Figure 11 The carbon CPMAS spectrum of amorphous PF-07220060 (Form 8) collected according to General Method 3 is shown. Chemical shifts are expressed in parts per million (ppm) and referenced to an external sample of solid-phase adamantane at 29.5 ppm. ssNMR of Form 8 is provided in ppm ± 0.2 ppm in Table 8. 13 List of C chemical shifts (ppm).

[0598] Table 8. ssNMR of amorphous PF-07220060 (Form 8) 13 C chemical shift (ppm)

[0599]

[0600]

[0601] Figure 12 The image shows amorphous PF-07220060 (form 8) collected according to general method 3. 19 F ss NMR spectra. Chemical shifts are expressed in parts per million (ppm) and their resonance is set to -76.54 ppm (as determined by pure TMS) with reference to an external standard of trifluoroacetic acid and water (50 / 50 volume / volume).

[0602] Table 9. List of 19F solid-state NMR peaks (ppm) for PF-07220060 hydrate (form 8).

[0603]

[0604] Example 11

[0605] Preparation of anhydrous crystallized PF-07220060 (Form 6)

[0606]

[0607] The amorphous PF-07220060 (form 8) (991.94 mg) prepared as described in Example 9 was added to a 20 mL vial equipped with a stir bar. Toluene (7.50 mL) was added and the mixture was heated to 100°C. After stirring at 100°C for 1 hour, the solid was collected by vacuum filtration (while hot) and dried under vacuum at 50°C to obtain anhydrous crystalline PF-07220060 (form 6). 614 mg, 62%.

[0608] Example 12

[0609] Characterization of anhydrous crystals PF-07220060 (Form 6)

[0610] The anhydrous crystalline PF-07220060 (form 6) prepared as described in Example 11 is characterized as follows:

[0611] PXRD data

[0612] Figure 13 The PXRD data collected according to general method 1A are shown. Table 10 provides a list of PXRD peaks with diffraction angles of 2-θ° (°2θ) ± 0.2°2θ and their relative intensities.

[0613] Table 10: PXRD peak list (2-θ°) of anhydrous crystallized PF-07220060 (form 6)

[0614]

[0615]

[0616] FT-Raman Data

[0617] Figure 14 The FT-Raman spectra of anhydrous crystalline PF-07220060 (form 6) collected according to general method 2 are shown in Table 11. The spectra are expressed in cm⁻¹. -1 ±2cm -1 Provides FT-Raman Peak (cm) -1 A complete list of normalized peak intensities is provided. The following indicates the normalized peak intensities: w = weak; m = moderate; s = strong.

[0618] Table 11. List of FT Raman peaks (cm) for anhydrous crystallized PF-07220060 (Form 6)-1 )

[0619]

[0620]

[0621] ssNMR data

[0622] Figure 15 The carbon CPMAS spectrum of anhydrous crystalline PF-07220060 (Form 6) collected according to General Method 3 is shown. Chemical shifts are expressed in parts per million (ppm) and referenced to an external sample of solid-phase adamantane at 29.5 ppm. SSNMR of Form 6 is provided in ppm ± 0.2 ppm in Table 12. 13 List of C chemical shifts (ppm).

[0623] Table 12: ssNMR of anhydrous crystalline PF-07220060 (form 6) 13 C chemical shift (ppm)

[0624]

[0625] Figure 16 The anhydrous crystals PF-07220060 (form 6) collected according to general method 3 are shown. 19 F ssNMR spectra. Chemical shifts are expressed in parts per million (ppm) and their resonance is set to -76.54 ppm (as determined by pure TMS) with reference to an external standard of trifluoroacetic acid and water (50 / 50 volume / volume). ssNMR spectra of Form 6 are provided in ppm ± 0.2 ppm in Table 13. 19 List of F chemical shifts (ppm).

[0626] Table 13. Anhydrous crystallization PF-07220060 (Form 6) 19 F solid-state NMR peak list (ppm).

[0627] Example 13

[0628] Preparation of anhydrous crystalline PF-07220060 (Form 11)

[0629]

[0630] The PF-07220060 monohydrate (form 2) (1.8 g) prepared as described in Example 2 was dehydrated under vacuum at 75°C for 4 days to obtain anhydrous crystalline PF-07220060 (form 11).

[0631] Characterization of Form 11 via PXRD:

[0632] Figure 17 The PXRD data of anhydrous crystals PF-07220060 (Form 11) collected according to general method 1A are shown.

[0633] Example 14

[0634] Solid-state stability analysis of PF-07220060 monohydrate (form 2)

[0635] The accelerated solid-state chemical and photostable stability of PF-07220060 monohydrate (form 2) was investigated. The solid-state chemical / humidity stability of PF-07220060 monohydrate (form 2) was evaluated by UPLC (ultra-high performance liquid chromatography) after storage for one week at 70°C / 5%RH and 70°C / 75%RH, and after six weeks at 40°C / 5%RH and 40°C / 75%RH. The percentage of identified impurity peaks at specified RRT (relative retention time) values ​​was determined under challenge conditions relative to a control sample stored at ambient temperature. RRT was calculated by dividing the retention time (RT) of the impurity by the RT of form 2. Data for one week at 70°C / 5%RH and 70°C / 75%RH are provided in Tables 14 and 15, respectively.

[0636] Table 14. Stability test of PF-07220060 monohydrate (form 2) at 70℃ / 5%RH

[0637]

[0638] Table 15. Stability test of PF-07220060 monohydrate (form 2) at 70℃ / 75%RH

[0639]

[0640] No significant changes in appearance were observed in any of the pressurized samples (i.e., one week at 70°C / 75% RH and 70°C / 5% RH, or six weeks at 40°C / 75% RH and 40°C / 5% RH) compared to the control samples. Individual impurity growth did not exceed 0.2%, and total impurities in the pressurized samples did not exceed 2.0%.

[0641] Powder X-ray diffraction was used to evaluate the solid form of the control and pressurized samples. No change in form was detected after storing PF-07220060 monohydrate (form 2) at 70°C / 75% RH for one week or at 40°C / 75% RH for six weeks. Under elevated temperature and low humidity conditions, slight disorder was observed after storing PF-07220060 monohydrate (form 2) at 70°C / 5% RH for one week, and disorder was observed after storing at 40°C / 5% RH for six weeks.

[0642] The solid-state photostability of PF-07220060 monohydrate (form 2) was evaluated after light exposure equivalent to the 2x International Conference on Harmonisation (ICH) guidelines. No significant changes in appearance were observed in the 2x ICH photostability samples compared to the foil-wrapped dark control samples. Individual impurity growth did not exceed 0.2%, and the total impurities in the 2x ICH photostability samples did not exceed 2.0%. Powder X-ray diffraction evaluation of the control and compressed samples confirmed the absence of form changes under 2x ICH conditions. Photostability data are provided in Table 16.

[0643] Table 16. Light stability test of PF-07220060 monohydrate (form 2)

[0644]

[0645] NMT = not exceeding

[0646] Example 15

[0647] Water adsorption analysis of PF-07220060 monohydrate (form 2)

[0648] Water adsorption and desorption studies were conducted on the PF-07220060 monohydrate (form 2) prepared as described in Example 2, according to general method 6. Data are provided in Table 17.

[0649] Table 17. Water adsorption analysis of PF-07220060 monohydrate (form 2).

[0650] Temperature (°C) RH (%) Weight increase (%) 60 0 0.00 25 0 0.00 25 10 0.45 25 20 0.49 25 30 0.51 25 40 0.52 25 50 0.54 25 60 0.56 25 70 0.57 25 80 0.59 25 90 0.62 25 80 0.61 25 70 0.60 25 60 0.60 25 50 0.58 25 40 0.57 25 30 0.56 25 20 0.55 25 10 0.54

[0651] Example 16

[0652] Water adsorption analysis of PF-07220060 hydrate (form 1)

[0653] Water adsorption and desorption studies were conducted on the PF-07220060 hydrate (form 1) prepared as described in Example 5B according to general method 6. Data are provided in Table 18.

[0654] Table 18. Water adsorption analysis of PF-07220060 hydrate (form 1)

[0655] Temperature (°C) RH (%) Weight increase (%) 60 0 0.00 25 0 0.05 25 10 1.23 25 20 2.34 25 30 2.84 25 40 3.10 25 50 3.26 25 60 3.37 25 70 3.46 25 80 3.53 25 90 3.61 25 80 3.55 25 70 3.49 25 60 3.41 25 50 3.30 25 40 3.13 25 30 2.87 25 20 2.38 25 10 1.26

[0656] Example 17

[0657] Comparison of hygroscopic properties

[0658] Hygroscopicity experiments were compared using moisture adsorption analysis according to General Method 6. Data are summarized in Table 19. Forms 1, 2, 6, and 8 of PF-07220060 were evaluated using moisture adsorption at 25°C and 60% RH. For any of the forms, no change in form was detected by PXRD at the end of the run. Forms 2 and 6 showed reduced hygroscopicity and significantly less weight gain relative to forms 8 and 1, with forms 8 and 1 exhibiting the highest weight gain.

[0659] Table 19. Comparison of water adsorption data for forms 1, 2, 6, and 8

[0660]

[0661] Example 18

[0662] Competitive slurry experiment

[0663] Competitive slurry experiments were conducted in 2-propanol / 1% water between Form 1 and Form 2 (item 1), and between Form 6 and Form 2 (item 2). Data are summarized in Table 20.

[0664] Item 1: PF-07220060 hydrate (form 1) (64.3 mg), PF-07220060 monohydrate (form 2) (67.7 mg), 2-propanol (0.990 mL), and water (0.010 mL) were stirred at room temperature for 15 hours. The solids were collected by vacuum filtration and analyzed by PXRD. The PXRD data were consistent with those of PF-07220060 monohydrate (form 2).

[0665] Item 2: Anhydrous PF-07220060 (form 6) (56.5 mg), PF-07220060 monohydrate (form 2) (59.4 mg), 2-propanol (0.990 mL), and water (0.010 mL) were stirred at room temperature for 15 hours. The solids were collected by vacuum filtration and analyzed by PXRD. The PXRD data were consistent with those of PF-07220060 monohydrate (form 2).

[0666] Forms 1 and 6 are converted to form 2 in a competing slurry in 2-propanol / 1% water. Based on the competing slurry experiment, form 2 is thermodynamically stable above 15% RH.

[0667] Table 20. Overview of the competitive slurry experiment in 2-propanol / 1% water.

[0668] entry Entry Form Output format 1 Form 1 + Form 2 Form 2 2 Form 6 + Form 2 Form 2

[0669] Example 19

[0670] Comparative thermal stability experiment

[0671] Thermal stability data were obtained by thermogravimetric analysis (TGA) according to general method 4 and differential scanning calorimetry (DSC) according to general method 5A. The data are shown in Table 21. Forms 6 and 2 show improved thermal stability compared to forms 1 and 8.

[0672] Table 21. Thermal stability data for forms 1, 2, 6 and 8

[0673]

[0674] Modifications may be made to the above without departing from the basic aspects of the invention. Although the invention has been described in substantial detail with reference to one or more specific embodiments, those skilled in the art will recognize that changes may be made to the embodiments specifically disclosed in this application, and such modifications and improvements remain within the scope and spirit of the invention.

Claims

1. A crystalline form (form 2) of 1,5-dehydrated-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol monohydrate, having a powder X-ray diffraction (PXRD) pattern of peaks containing 2θ values ​​at 9.6, 11.8, 12.4 and 14.7 °2θ ± 0.2 °2θ.

2. The crystalline form as claimed in claim 1, having a PXRD pattern of a peak further comprising a 2θ value of 21.0 °2θ ± 0.2 °2θ.

3. The crystalline form as described in claim 1, having 1484, 1555, and 1587 cm⁻¹ -1 ± 2 cm -1 Raman spectra of wave values.

4. The crystalline form as described in claim 3, further comprising 1387 cm⁻¹ -1 ± 2 cm -1 Raman spectra of wave values.

5. The crystalline form as described in claim 3, further comprising 1395 cm⁻¹ -1 ± 2 cm -1 Raman spectra of wave values.

6. The crystalline form as claimed in any one of claims 1 to 5, having resonance values ​​comprising 22.8 and 163.0 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

7. The crystalline form as claimed in claim 6, having additional resonance values ​​comprising one, two, or three values ​​selected from the group consisting of 50.3, 109.8, and 129.1 ppm ± 0.2 ppm. 13 C solid-state NMR spectroscopy.

8. The crystalline form as claimed in any one of claims 1 to 5, having a resonance value comprising -126.1 ppm ± 0.2 ppm. 19 F solid-state NMR spectrum.

9. The crystalline form as claimed in any one of claims 1 to 5, having an additional resonance value comprising -125.6 ppm ± 0.2 ppm. 19 F solid-state NMR spectroscopy.

10. A crystalline form (form 2) of 1,5-dehydrated-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropyl-2-yl)-1-(propyl-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol monohydrate, having: (a) a powder X-ray diffraction (PXRD) pattern containing peaks at 2θ values ​​of 9.6, 11.8, 12.4, and 14.7 °2θ ± 0.2 °2θ; and optionally one or more of the following: (b) peaks containing 1484, 1555, and 1587 cm⁻¹. -1 ± 2 cm -1 (c) Raman spectra of wave values ​​of 22.8 and 163.0 ppm ± 0.2 ppm; 13 (c) solid-state NMR spectra; and (d) resonance values ​​containing -126.1 and -125.6 ppm ± 0.2 ppm. 19 F solid-state NMR spectroscopy.

11. The crystalline form of any one of claims 1 to 5, wherein the crystalline form contains less than 5% impurities.

12. A pharmaceutical composition comprising a crystalline form as claimed in any one of claims 1 to 11, and a pharmaceutically acceptable carrier or excipient.

13. Use of the crystalline form of any one of claims 1 to 11 in the preparation of a medicament for treating cancer, wherein the cancer is characterized by amplification or overexpression of CDK4 and / or CDK6.

14. The use as claimed in claim 13, wherein the cancer is selected from the group consisting of: breast cancer, prostate cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, uterine cancer, pancreatic cancer, stomach cancer, colorectal cancer, esophageal cancer, head and neck cancer, testicular cancer, adrenal cancer, skin cancer, brain cancer, sarcoma, and lymphoma.

15. The crystalline form of any one of claims 1 to 11, for the treatment of cancer, wherein the cancer is characterized by amplification or overexpression of CDK4 and / or CDK6.

16. The crystalline form of claim 15, wherein the cancer is selected from the group consisting of: breast cancer, prostate cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, uterine cancer, pancreatic cancer, stomach cancer, colorectal cancer, esophageal cancer, head and neck cancer, testicular cancer, adrenal cancer, skin cancer, brain cancer, sarcoma, and lymphoma.

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